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1. The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum.

Author

Watson, Savannah J., van der Watt, Mariëtte E., Theron, Anjo, Reader, Janette, Tshabalala, Sizwe, Erlank, Erica, Koekemoer, Lizette L., Naude, Mariska, Stampolaki, Marianna, Adewole, Feyisola, Sadowska, Katie, Pérez-Lozano, Pilar, Turcu, Andreea L., Vázquez, Santiago, Ko, Jihee, Mazurek, Ben, Singh, Davinder, Malwal, Satish R., Njoroge, Mathew, and Chibale, Kelly

Published
2024
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2. Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Author

Reader, Janette, van der Watt, Mariëtte E., Taylor, Dale, Le Manach, Claire, Mittal, Nimisha, Ottilie, Sabine, Theron, Anjo, Moyo, Phanankosi, Erlank, Erica, Nardini, Luisa, Venter, Nelius, Lauterbach, Sonja, Bezuidenhout, Belinda, Horatscheck, Andre, van Heerden, Ashleigh, Spillman, Natalie J., Cowell, Anne N., Connacher, Jessica, Opperman, Daniel, Orchard, Lindsey M., Llinás, Manuel, Istvan, Eva S., Goldberg, Daniel E., Boyle, Grant A., Calvo, David, Mancama, Dalu, Coetzer, Theresa L., Winzeler, Elizabeth A., Duffy, James, Koekemoer, Lizette L., Basarab, Gregory, Chibale, Kelly, and Birkholtz, Lyn-Marié

Published
2021
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3. New Transmission‐Selective Antimalarial Agents through Hit‐to‐Lead Optimization of 2‐([1,1′‐Biphenyl]‐4‐carboxamido)benzoic Acid Derivatives

Author

Reader, Janette, primary, Opperman, Daniel F. L., additional, van der Watt, Mariëtte E., additional, Theron, Anjo, additional, Leshabane, Meta, additional, da Rocha, Shanté, additional, Turner, Jonathan, additional, Garrabrant, Kathleen, additional, Piña, Ivett, additional, Mills, Catherine, additional, Woster, Patrick M., additional, and Birkholtz, Lyn‐Marié, additional

Published
2022
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4. Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts

Author

Le Manach, Claire, primary, Dam, Jean, additional, Woodland, John G., additional, Kaur, Gurminder, additional, Khonde, Lutete P., additional, Brunschwig, Christel, additional, Njoroge, Mathew, additional, Wicht, Kathryn J., additional, Horatscheck, André, additional, Paquet, Tanya, additional, Boyle, Grant A., additional, Gibhard, Liezl, additional, Taylor, Dale, additional, Lawrence, Nina, additional, Yeo, Tomas, additional, Mok, Sachel, additional, Eastman, Richard T., additional, Dorjsuren, Dorjbal, additional, Talley, Daniel C., additional, Guo, Hui, additional, Simeonov, Anton, additional, Reader, Janette, additional, van der Watt, Mariëtte, additional, Erlank, Erica, additional, Venter, Nelius, additional, Zawada, Jacek W., additional, Aswat, Ayesha, additional, Nardini, Luisa, additional, Coetzer, Theresa L., additional, Lauterbach, Sonja B., additional, Bezuidenhout, Belinda C., additional, Theron, Anjo, additional, Mancama, Dalu, additional, Koekemoer, Lizette L., additional, Birkholtz, Lyn-Marie, additional, Wittlin, Sergio, additional, Delves, Michael, additional, Ottilie, Sabine, additional, Winzeler, Elizabeth A., additional, von Geldern, Thomas W., additional, Smith, Dennis, additional, Fidock, David A., additional, Street, Leslie J., additional, Basarab, Gregory S., additional, Duffy, James, additional, and Chibale, Kelly, additional

Published
2021
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5. Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Author

Reader, Janette, primary, van der Watt, Mariёtte E., additional, Taylor, Dale, additional, Le Manach, Claire, additional, Mittal, Nimisha, additional, Ottilie, Sabine, additional, Theron, Anjo, additional, Moyo, Phanankosi, additional, Erlank, Erica, additional, Nardini, Luisa, additional, Venter, Nelius, additional, Lauterbach, Sonja, additional, Bezuidenhout, Belinda, additional, Horatscheck, Andre, additional, van Heerden, Ashleigh, additional, Boyle, Grant A., additional, Calvo, David, additional, Mancama, Dalu, additional, Coetzer, Theresa L., additional, Winzeler, Elizabeth A., additional, Duffy, James, additional, Koekemoer, Lizette L., additional, Basarab, Gregory, additional, Chibale, Kelly, additional, and Birkholtz, Lyn-Marié, additional

Published
2020
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7. Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials

Author

van der Watt, Mariëtte E, primary, Reader, Janette, additional, Churchyard, Alisje, additional, Nondaba, Sindisiwe H, additional, Lauterbach, Sonja B, additional, Niemand, Jandeli, additional, Abayomi, Sijuade, additional, van Biljon, Riëtte A, additional, Connacher, Jessica I, additional, van Wyk, Roelof D J, additional, Le Manach, Claire, additional, Paquet, Tanya, additional, González Cabrera, Diego, additional, Brunschwig, Christel, additional, Theron, Anjo, additional, Lozano-Arias, Sonia, additional, Rodrigues, Janneth F I, additional, Herreros, Esperanza, additional, Leroy, Didier, additional, Duffy, James, additional, Street, Leslie J, additional, Chibale, Kelly, additional, Mancama, Dalu, additional, Coetzer, Theresa L, additional, and Birkholtz, Lyn-Marie, additional

Published
2018
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9. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

Author

Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Bhatia, Sangeeta N, Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Yesmalie, Alemán Resto, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Cassera, Maria Belen, Ken, Chih-Chien Cheng, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D’Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H. Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R. Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, Willis, Paul A., Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Bhatia, Sangeeta N, Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Yesmalie, Alemán Resto, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Cassera, Maria Belen, Ken, Chih-Chien Cheng, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D’Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H. Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R. Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, and Willis, Paul A.

Abstract

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemis

Published
2017

10. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

Author

Phillips, Margaret A., Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H.Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Abdo Rizk, Mohamed, Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R.Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, and Willis, Paul A.

Abstract

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

Published
2016

11. Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparumand Optimization Efforts

Author

Le Manach, Claire, Dam, Jean, Woodland, John G., Kaur, Gurminder, Khonde, Lutete P., Brunschwig, Christel, Njoroge, Mathew, Wicht, Kathryn J., Horatscheck, André, Paquet, Tanya, Boyle, Grant A., Gibhard, Liezl, Taylor, Dale, Lawrence, Nina, Yeo, Tomas, Mok, Sachel, Eastman, Richard T., Dorjsuren, Dorjbal, Talley, Daniel C., Guo, Hui, Simeonov, Anton, Reader, Janette, van der Watt, Mariëtte, Erlank, Erica, Venter, Nelius, Zawada, Jacek W., Aswat, Ayesha, Nardini, Luisa, Coetzer, Theresa L., Lauterbach, Sonja B., Bezuidenhout, Belinda C., Theron, Anjo, Mancama, Dalu, Koekemoer, Lizette L., Birkholtz, Lyn-Marie, Wittlin, Sergio, Delves, Michael, Ottilie, Sabine, Winzeler, Elizabeth A., von Geldern, Thomas W., Smith, Dennis, Fidock, David A., Street, Leslie J., Basarab, Gregory S., Duffy, James, and Chibale, Kelly

Abstract

A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparumwhole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp3-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure–activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (<50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparumcyclic amine resistance locus in the mode of resistance.

Published
2021
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12. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

Author

Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Resto, Yesmalie Aleman, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Juergen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Cassera, Maria B., Cheng, Ken Chih-Chien, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colon-Lopez, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D'Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, El-Sayed, Shimaa Abd El-Salam, Ferdig, Michael T., Robledo, Jose A. Fernandez, Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Javier Gamo, Francisco, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, van Huijsduijnen, Rob Hooft, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Jensen, Amornrat Naranuntarat, Jensen, Laran T., Jiang, Rays H. Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Jose Lafuente, Maria, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinas, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Vera, Iset Medina, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Rodrigues da Costa, Francielly Morais, Mueller, Joachim, Muriana, Arantza, Hewitt, Stephen Nakazawa, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Ngoc Pham, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Rizk, Mohamed Abdo, Ruecker, Andrea, St Onge, Robert, Ferreira, Rafaela Salgado, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Villela, Filipe Silva, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmueller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William G., Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R. Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Phat Voong Vinh, Hoan Vu, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoit, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, Willis, Paul A., Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Resto, Yesmalie Aleman, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Juergen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Cassera, Maria B., Cheng, Ken Chih-Chien, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colon-Lopez, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D'Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, El-Sayed, Shimaa Abd El-Salam, Ferdig, Michael T., Robledo, Jose A. Fernandez, Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Javier Gamo, Francisco, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, van Huijsduijnen, Rob Hooft, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Jensen, Amornrat Naranuntarat, Jensen, Laran T., Jiang, Rays H. Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Jose Lafuente, Maria, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinas, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Vera, Iset Medina, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Rodrigues da Costa, Francielly Morais, Mueller, Joachim, Muriana, Arantza, Hewitt, Stephen Nakazawa, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Ngoc Pham, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Rizk, Mohamed Abdo, Ruecker, Andrea, St Onge, Robert, Ferreira, Rafaela Salgado, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Villela, Filipe Silva, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmueller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William G., Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R. Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Phat Voong Vinh, Hoan Vu, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoit, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, and Willis, Paul A.

Abstract

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemis

Published
2016
Full Text
View/download PDF

13. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

Author

Biochemistry, Center for Drug Discovery, Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Resto, Yesmalie Aleman, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Juergen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Cassera, Maria B., Cheng, Ken Chih-Chien, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colon-Lopez, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D'Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, El-Sayed, Shimaa Abd El-Salam, Ferdig, Michael T., Robledo, Jose A. Fernandez, Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Javier Gamo, Francisco, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, van Huijsduijnen, Rob Hooft, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Jensen, Amornrat Naranuntarat, Jensen, Laran T., Jiang, Rays H. Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Jose Lafuente, Maria, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinas, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Vera, Iset Medina, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Rodrigues da Costa, Francielly Morais, Mueller, Joachim, Muriana, Arantza, Hewitt, Stephen Nakazawa, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Ngoc Pham, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Rizk, Mohamed Abdo, Ruecker, Andrea, St Onge, Robert, Ferreira, Rafaela Salgado, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Villela, Filipe Silva, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmueller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William G., Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R. Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Phat Voong Vinh, Hoan Vu, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoit, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, Willis, Paul A., Biochemistry, Center for Drug Discovery, Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Resto, Yesmalie Aleman, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Juergen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Cassera, Maria B., Cheng, Ken Chih-Chien, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colon-Lopez, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D'Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, El-Sayed, Shimaa Abd El-Salam, Ferdig, Michael T., Robledo, Jose A. Fernandez, Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Javier Gamo, Francisco, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, van Huijsduijnen, Rob Hooft, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Jensen, Amornrat Naranuntarat, Jensen, Laran T., Jiang, Rays H. Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Jose Lafuente, Maria, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinas, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Vera, Iset Medina, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Rodrigues da Costa, Francielly Morais, Mueller, Joachim, Muriana, Arantza, Hewitt, Stephen Nakazawa, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Ngoc Pham, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Rizk, Mohamed Abdo, Ruecker, Andrea, St Onge, Robert, Ferreira, Rafaela Salgado, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Villela, Filipe Silva, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmueller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William G., Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R. Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Phat Voong Vinh, Hoan Vu, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoit, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, and Willis, Paul A.

Abstract

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemis

Published
2016

14. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

Author

Van Voorhis, Wesley C., primary, Adams, John H., additional, Adelfio, Roberto, additional, Ahyong, Vida, additional, Akabas, Myles H., additional, Alano, Pietro, additional, Alday, Aintzane, additional, Alemán Resto, Yesmalie, additional, Alsibaee, Aishah, additional, Alzualde, Ainhoa, additional, Andrews, Katherine T., additional, Avery, Simon V., additional, Avery, Vicky M., additional, Ayong, Lawrence, additional, Baker, Mark, additional, Baker, Stephen, additional, Ben Mamoun, Choukri, additional, Bhatia, Sangeeta, additional, Bickle, Quentin, additional, Bounaadja, Lotfi, additional, Bowling, Tana, additional, Bosch, Jürgen, additional, Boucher, Lauren E., additional, Boyom, Fabrice F., additional, Brea, Jose, additional, Brennan, Marian, additional, Burton, Audrey, additional, Caffrey, Conor R., additional, Camarda, Grazia, additional, Carrasquilla, Manuela, additional, Carter, Dee, additional, Belen Cassera, Maria, additional, Chih-Chien Cheng, Ken, additional, Chindaudomsate, Worathad, additional, Chubb, Anthony, additional, Colon, Beatrice L., additional, Colón-López, Daisy D., additional, Corbett, Yolanda, additional, Crowther, Gregory J., additional, Cowan, Noemi, additional, D’Alessandro, Sarah, additional, Le Dang, Na, additional, Delves, Michael, additional, DeRisi, Joseph L., additional, Du, Alan Y., additional, Duffy, Sandra, additional, Abd El-Salam El-Sayed, Shimaa, additional, Ferdig, Michael T., additional, Fernández Robledo, José A., additional, Fidock, David A., additional, Florent, Isabelle, additional, Fokou, Patrick V. T., additional, Galstian, Ani, additional, Gamo, Francisco Javier, additional, Gokool, Suzanne, additional, Gold, Ben, additional, Golub, Todd, additional, Goldgof, Gregory M., additional, Guha, Rajarshi, additional, Guiguemde, W. Armand, additional, Gural, Nil, additional, Guy, R. Kiplin, additional, Hansen, Michael A. E., additional, Hanson, Kirsten K., additional, Hemphill, Andrew, additional, Hooft van Huijsduijnen, Rob, additional, Horii, Takaaki, additional, Horrocks, Paul, additional, Hughes, Tyler B., additional, Huston, Christopher, additional, Igarashi, Ikuo, additional, Ingram-Sieber, Katrin, additional, Itoe, Maurice A., additional, Jadhav, Ajit, additional, Naranuntarat Jensen, Amornrat, additional, Jensen, Laran T., additional, Jiang, Rays H. Y., additional, Kaiser, Annette, additional, Keiser, Jennifer, additional, Ketas, Thomas, additional, Kicka, Sebastien, additional, Kim, Sunyoung, additional, Kirk, Kiaran, additional, Kumar, Vidya P., additional, Kyle, Dennis E., additional, Lafuente, Maria Jose, additional, Landfear, Scott, additional, Lee, Nathan, additional, Lee, Sukjun, additional, Lehane, Adele M., additional, Li, Fengwu, additional, Little, David, additional, Liu, Liqiong, additional, Llinás, Manuel, additional, Loza, Maria I., additional, Lubar, Aristea, additional, Lucantoni, Leonardo, additional, Lucet, Isabelle, additional, Maes, Louis, additional, Mancama, Dalu, additional, Mansour, Nuha R., additional, March, Sandra, additional, McGowan, Sheena, additional, Medina Vera, Iset, additional, Meister, Stephan, additional, Mercer, Luke, additional, Mestres, Jordi, additional, Mfopa, Alvine N., additional, Misra, Raj N., additional, Moon, Seunghyun, additional, Moore, John P., additional, Morais Rodrigues da Costa, Francielly, additional, Müller, Joachim, additional, Muriana, Arantza, additional, Nakazawa Hewitt, Stephen, additional, Nare, Bakela, additional, Nathan, Carl, additional, Narraidoo, Nathalie, additional, Nawaratna, Sujeevi, additional, Ojo, Kayode K., additional, Ortiz, Diana, additional, Panic, Gordana, additional, Papadatos, George, additional, Parapini, Silvia, additional, Patra, Kailash, additional, Pham, Ngoc, additional, Prats, Sarah, additional, Plouffe, David M., additional, Poulsen, Sally-Ann, additional, Pradhan, Anupam, additional, Quevedo, Celia, additional, Quinn, Ronald J., additional, Rice, Christopher A., additional, Abdo Rizk, Mohamed, additional, Ruecker, Andrea, additional, St. Onge, Robert, additional, Salgado Ferreira, Rafaela, additional, Samra, Jasmeet, additional, Robinett, Natalie G., additional, Schlecht, Ulrich, additional, Schmitt, Marjorie, additional, Silva Villela, Filipe, additional, Silvestrini, Francesco, additional, Sinden, Robert, additional, Smith, Dennis A., additional, Soldati, Thierry, additional, Spitzmüller, Andreas, additional, Stamm, Serge Maximilian, additional, Sullivan, David J., additional, Sullivan, William, additional, Suresh, Sundari, additional, Suzuki, Brian M., additional, Suzuki, Yo, additional, Swamidass, S. Joshua, additional, Taramelli, Donatella, additional, Tchokouaha, Lauve R. Y., additional, Theron, Anjo, additional, Thomas, David, additional, Tonissen, Kathryn F., additional, Townson, Simon, additional, Tripathi, Abhai K., additional, Trofimov, Valentin, additional, Udenze, Kenneth O., additional, Ullah, Imran, additional, Vallieres, Cindy, additional, Vigil, Edgar, additional, Vinetz, Joseph M., additional, Voong Vinh, Phat, additional, Vu, Hoan, additional, Watanabe, Nao-aki, additional, Weatherby, Kate, additional, White, Pamela M., additional, Wilks, Andrew F., additional, Winzeler, Elizabeth A., additional, Wojcik, Edward, additional, Wree, Melanie, additional, Wu, Wesley, additional, Yokoyama, Naoaki, additional, Zollo, Paul H. A., additional, Abla, Nada, additional, Blasco, Benjamin, additional, Burrows, Jeremy, additional, Laleu, Benoît, additional, Leroy, Didier, additional, Spangenberg, Thomas, additional, Wells, Timothy, additional, and Willis, Paul A., additional

Published
2016
Full Text
View/download PDF

15. Nowhere to hide: interrogating different metabolic parameters of Plasmodium falciparum gametocytes in a transmission blocking drug discovery pipeline towards malaria elimination

Author

Reader, Janette, primary, Botha, Mariëtte, additional, Theron, Anjo, additional, Lauterbach, Sonja B, additional, Rossouw, Claire, additional, Engelbrecht, Dewaldt, additional, Wepener, Melanie, additional, Smit, Annél, additional, Leroy, Didier, additional, Mancama, Dalu, additional, Coetzer, Theresa L, additional, and Birkholtz, Lyn-Marie, additional

Published
2015
Full Text
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16. Open source drug discovery with the malaria box compound collection for neglected diseases and beyond

Author

Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Alemán Resto, Yesmalie, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D'Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H. Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Abdo Rizk, Mohamed, Ruecker, Andrea, St Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R. Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-Aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, and Willis, Paul A.

Subjects
3. Good health

17. Open source drug discovery with the Malaria Box Compound collection for neglected diseases and beyond

Author

Phillips, Margaret A., Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Alemán Resto, Yesmalie, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D’Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H.Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Abdo Rizk, Mohamed, Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R.Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, Willis, Paul A., Phillips, Margaret A., Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Alemán Resto, Yesmalie, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D’Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H.Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Abdo Rizk, Mohamed, Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R.Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, and Willis, Paul A.

Abstract

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemis

Full Text
View/download PDF

18. Open source drug discovery with the Malaria Box Compound collection for neglected diseases and beyond

Author

Phillips, Margaret A., Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Alemán Resto, Yesmalie, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D’Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H.Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Abdo Rizk, Mohamed, Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R.Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, Willis, Paul A., Phillips, Margaret A., Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Alemán Resto, Yesmalie, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D’Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H.Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Abdo Rizk, Mohamed, Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R.Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, and Willis, Paul A.

Abstract

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemis

Full Text
View/download PDF

19. Open source drug discovery with the Malaria Box Compound collection for neglected diseases and beyond

Author

Phillips, Margaret A., Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Alemán Resto, Yesmalie, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D’Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H.Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Abdo Rizk, Mohamed, Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R.Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, Willis, Paul A., Phillips, Margaret A., Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Alemán Resto, Yesmalie, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D’Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H.Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Abdo Rizk, Mohamed, Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R.Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, and Willis, Paul A.

Abstract

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemis

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20. Open source drug discovery with the Malaria Box Compound collection for neglected diseases and beyond

Author

Phillips, Margaret A., Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Alemán Resto, Yesmalie, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D’Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H.Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Abdo Rizk, Mohamed, Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R.Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, Willis, Paul A., Phillips, Margaret A., Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Alemán Resto, Yesmalie, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bhatia, Sangeeta, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, Daisy D., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, D’Alessandro, Sarah, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, Gokool, Suzanne, Gold, Ben, Golub, Todd, Goldgof, Gregory M., Guha, Rajarshi, Guiguemde, W. Armand, Gural, Nil, Guy, R. Kiplin, Hansen, Michael A. E., Hanson, Kirsten K., Hemphill, Andrew, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, Jensen, Laran T., Jiang, Rays H.Y., Kaiser, Annette, Keiser, Jennifer, Ketas, Thomas, Kicka, Sebastien, Kim, Sunyoung, Kirk, Kiaran, Kumar, Vidya P., Kyle, Dennis E., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Abdo Rizk, Mohamed, Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, Suresh, Sundari, Suzuki, Brian M., Suzuki, Yo, Swamidass, S. Joshua, Taramelli, Donatella, Tchokouaha, Lauve R.Y., Theron, Anjo, Thomas, David, Tonissen, Kathryn F., Townson, Simon, Tripathi, Abhai K., Trofimov, Valentin, Udenze, Kenneth O., Ullah, Imran, Vallieres, Cindy, Vigil, Edgar, Vinetz, Joseph M., Voong Vinh, Phat, Vu, Hoan, Watanabe, Nao-aki, Weatherby, Kate, White, Pamela M., Wilks, Andrew F., Winzeler, Elizabeth A., Wojcik, Edward, Wree, Melanie, Wu, Wesley, Yokoyama, Naoaki, Zollo, Paul H. A., Abla, Nada, Blasco, Benjamin, Burrows, Jeremy, Laleu, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, and Willis, Paul A.

Abstract

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemis

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21. Beskrywing, modellering en dok-studies van Plasmodium falciparum kinase PfCDPK4.

Author

Makungoa, Thomas, Tsekoa, Tsepo, Theron, Anjo, Mancama, Dalu, and van Ree, Teunis

Abstract

Characterization, modelling and docking studies of Plasmodium falciparum kinase PfCDPK4: The increasing incidence of Plasmodium strains that are resistant to current frontline antimalarial drugs has become one of the greatest challenges of controlling malaria incidence and mortality. There is, therefore, an urgent need to develop novel targets and antimalarial drugs that are effective against drug-resistant malarial parasites. At the same time the need to develop antimalarial drugs that furthermore prevent disease transmission, has become an increasingly important consideration. Calcium dependent protein kinases (CDPKs) regulate a variety of biological processes in the malaria parasite Plasmodium falciparum, CDPK4 being of prime importance in Plasmodium biology. In this study the structure of PfCDPK4 was used as a template in the discovery of malaria drug leads. The model structure of PfCDPK4 was generated by homology modelling, and model validation confirmed that the model of PfCDPK4 is of stereochemical quality. The molecular modelling approach of in silico screening against the target molecule PfCDPK4 utilized a large library of chemical compounds, some natural chemical compounds, and clinically approved kinase inhibitors. In silico screening of the Biofocus library against PfCDPK4 resulted in twenty-six compounds being identified; in vitro screening confirmed that three of these compounds exhibit moderate antimalarial activity against the NF54 strain of Plasmodium falciparum, with the percentage inhibition ranging between 42% and 47%. [ABSTRACT FROM AUTHOR]

Published
2019

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