Search

Your search keyword '"Bolotokova A"' showing total 21 results
Start Over Author "Bolotokova A" Publication Year Range Last 3 years
21 results on '"Bolotokova A"'

2. A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization

Author

Dilworth, David, Hanley, Ronan P., Ferreira de Freitas, Renato, Allali-Hassani, Abdellah, Zhou, Mengqi, Mehta, Naimee, Marunde, Matthew R., Ackloo, Suzanne, Carvalho Machado, Raquel Arminda, Khalili Yazdi, Aliakbar, Owens, Dominic D. G., Vu, Victoria, Nie, David Y., Alqazzaz, Mona, Marcon, Edyta, Li, Fengling, Chau, Irene, Bolotokova, Albina, Qin, Su, Lei, Ming, Liu, Yanli, Szewczyk, Magdalena M., Dong, Aiping, Kazemzadeh, Sina, Abramyan, Tigran, Popova, Irina K., Hall, Nathan W., Meiners, Matthew J., Cheek, Marcus A., Gibson, Elisa, Kireev, Dmitri, Greenblatt, Jack F., Keogh, Michael-C., Min, Jinrong, Brown, Peter J., Vedadi, Masoud, Arrowsmith, Cheryl H., Barsyte-Lovejoy, Dalia, James, Lindsey I., and Schapira, Matthieu

Published
2022
Full Text
View/download PDF

3. A resource to enable chemical biology and drug discovery of WDR Proteins

Author

Arrowsmith, Cheryl H, primary, Ackloo, Suzanne, additional, Li, Fengling, additional, Szewczyk, Magda, additional, Seitova, Almagul, additional, Loppnau, Peter, additional, Zeng, Hong, additional, Ahmad, Shabbir, additional, Beldar, Serap, additional, Bolotokova, Albina, additional, Chau, Irene, additional, Dehghani-Tafti, Saba, additional, Dong, Aiping, additional, Ghiabi, Pegah, additional, Gibson, Elisa, additional, Green, Stuart R, additional, Herasymenko, Oleksandra, additional, Houliston, Scott, additional, Hutchinson, Ashley, additional, Kimani, Serah W, additional, Kutera, Maria, additional, Kwak, Haejin A, additional, Li, Yanjun, additional, Machado, Raquel AC, additional, Perveen, Sumera, additional, Righetto, Germanna L, additional, Shrestha, Suman, additional, Silva, Madhushika, additional, Yadav, Manisha, additional, Yazdi, Aliakbar K, additional, Santhakumar, Vijayaratnam, additional, Edwards, Aled M, additional, Barsyte-Lovejoy, Dalia, additional, Schapira, Matthieu, additional, Brown, Peter J, additional, Halabelian, Levon, additional, Xu, Jin, additional, Feng, Jianwen A, additional, Kearnes, Steven, additional, Thompson, James, additional, Torng, Wen, additional, Gilmer, Justin, additional, Riley, Patrick, additional, Watson, Ian, additional, Arnautova, Yelena A, additional, Baghaie, AJ, additional, Cuozzo, John W, additional, Disch, Jeremy S, additional, Dumas, Antoine, additional, Harms, Nathan, additional, Liu, Jenny, additional, Sigel, Eric A, additional, Goldman, Brian, additional, Kramer, Trevor, additional, Mulhern, Christopher A, additional, Slakman, Belinda L, additional, Underkoffler, Carl, additional, von Rechenberg, Moritz, additional, Centrella, Paolo A, additional, Clark, Matthew A, additional, Guie, Marie-Aude, additional, Gullinger, John P, additional, Keefe, Anthony D, additional, Taylor, Rhys D, additional, Zhang, Junyi, additional, Zhang, Ying, additional, Lento, Cristina, additional, Wilson, Derek J, additional, Wolf, Esther, additional, Loup, Joachim, additional, and Sintchak, Michael D, additional

Published
2024
Full Text
View/download PDF

5. Discovery of a First-in-Class Small-Molecule Ligand for WDR91 Using DNA-Encoded Chemical Library Selection Followed by Machine Learning

Author

Ahmad, Shabbir, primary, Xu, Jin, additional, Feng, Jianwen A., additional, Hutchinson, Ashley, additional, Zeng, Hong, additional, Ghiabi, Pegah, additional, Dong, Aiping, additional, Centrella, Paolo A., additional, Clark, Matthew A., additional, Guié, Marie-Aude, additional, Guilinger, John P., additional, Keefe, Anthony D., additional, Zhang, Ying, additional, Cerruti, Thomas, additional, Cuozzo, John W., additional, von Rechenberg, Moritz, additional, Bolotokova, Albina, additional, Li, Yanjun, additional, Loppnau, Peter, additional, Seitova, Alma, additional, Li, Yen-Yen, additional, Santhakumar, Vijayaratnam, additional, Brown, Peter J., additional, Ackloo, Suzanne, additional, and Halabelian, Levon, additional

Published
2023
Full Text
View/download PDF

6. Development of LM-41 and AF-2112, two flufenamic acid-derived TEAD inhibitors obtained through the replacement of the trifluoromethyl group by aryl rings

Author

Fnaiche, Ahmed, primary, Mélin, Léa, additional, Suárez, Narjara González, additional, Paquin, Alexis, additional, Vu, Victoria, additional, Li, Fengling, additional, Allali-Hassani, Abdellah, additional, Bolotokova, Albina, additional, Allemand, Frédéric, additional, Gelin, Muriel, additional, Cotelle, Philippe, additional, Woo, Simon, additional, LaPlante, Steven R., additional, Barsyte-Lovejoy, Dalia, additional, Santhakumar, Vijayaratnam, additional, Vedadi, Masoud, additional, Guichou, Jean-François, additional, Annabi, Borhane, additional, and Gagnon, Alexandre, additional

Published
2023
Full Text
View/download PDF

8. Development of HC-258, a Covalent Acrylamide TEAD Inhibitor That Reduces Gene Expression and Cell Migration.

Author

Fnaiche, Ahmed, Chan, Hwai-Chien, Paquin, Alexis, González Suárez, Narjara, Vu, Victoria, Li, Fengling, Allali-Hassani, Abdellah, Cao, Michelle Ada, Szewczyk, Magdalena M., Bolotokova, Albina, Allemand, Frédéric, Gelin, Muriel, Barsyte-Lovejoy, Dalia, Santhakumar, Vijayaratnam, Vedadi, Masoud, Guichou, Jean-François, Annabi, Borhane, and Gagnon, Alexandre

Published
2023
Full Text
View/download PDF

9. SS148 and WZ16 inhibit the activities of nsp10-nsp16 complexes from all seven human pathogenic coronaviruses

Author

Li, Fengling, primary, Ghiabi, Pegah, additional, Hajian, Taraneh, additional, Klima, Martin, additional, Li, Alice Shi Ming, additional, Khalili Yazdi, Aliakbar, additional, Chau, Irene, additional, Loppnau, Peter, additional, Kutera, Maria, additional, Seitova, Almagul, additional, Bolotokova, Albina, additional, Hutchinson, Ashley, additional, Perveen, Sumera, additional, Boura, Evzen, additional, and Vedadi, Masoud, additional

Published
2023
Full Text
View/download PDF

10. A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization

Author

Marcus A. Cheek, Aiping Dong, Renato Ferreira de Freitas, Dalia Barsyte-Lovejoy, Aliakbar Khalili Yazdi, Jinrong Min, Fengling Li, Victoria Vu, Albina Bolotokova, Lindsey I. James, Jack Greenblatt, Naimee Mehta, Irina K. Popova, David Dilworth, Ming Lei, Raquel Arminda Carvalho Machado, Ronan P Hanley, David Y Nie, Matthieu Schapira, Mengqi Zhou, Elisa Gibson, Cheryl H. Arrowsmith, Michael-Christopher Keogh, Suzanne Ackloo, Matthew R. Marunde, Mona Alqazzaz, Dmitri Kireev, Nathan W. Hall, Peter Brown, Abdellah Allali-Hassani, Sina Kazemzadeh, Edyta Marcon, Tigran M. Abramyan, Dominic D G Owens, Yanli Liu, Magdalena M. Szewczyk, Matthew J. Meiners, Irene Chau, Su Qin, and Masoud Vedadi

Subjects
Gene isoform, Methyltransferase, Nucleolus, Lysine, Methylation, Article, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, Molecular Biology, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, biology, Chemistry, Histone-Lysine N-Methyltransferase, Cell Biology, Nucleosomes, Chromatin, Cell biology, Repressor Proteins, Histone, Enzyme, Molecular Probes, 030220 oncology & carcinogenesis, biology.protein, Multiple Myeloma, Cell Nucleolus
Abstract

Nuclear receptor-binding SET domain-containing 2 (NSD2) is the primary enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36), a mark associated with active gene transcription and intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two proline-tryptophan-tryptophan-proline (PWWP) domains and five plant homeodomains (PHDs) believed to serve as chromatin reading modules. Here, we report a chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1, antagonizes PWWP1 interaction with nucleosomal H3K36me2 and selectively engages endogenous NSD2 in cells. UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 that result from translocations prevalent in multiple myeloma (MM). Mutations of other NSD2 chromatin reader domains also increase NSD2 nucleolar localization and enhance the effect of UNC6934. This chemical probe and the accompanying negative control UNC7145 will be useful tools in defining NSD2 biology.

Published
2021

11. [Polypragmasia and interdrug interactions as risk factors of falling in elderly patients.]

Author

E S, Ilyina, V A, Shalygin, O T, Bogova, V N, Potapov, A V, Bolotokova, M I, Savelyeva, I I, Sinitsina, E V, Doskina, and D A, Sychev

Subjects
Risk Factors, Polypharmacy, Humans, Accidental Falls, Aged
Abstract

This article presents the results of the analysis of data from patients over 75 years of age from a multidisciplinary hospital with cardiovascular disease and comorbid conditions. Pharmacotherapy of gerontological patients with multiple risk factors for falls was analysed in terms of the presence of polypragmasy and drug-drug interactions hazardous to the risk of falls. In the group of patients who experienced a fall in hospital compared to patients without a fall, the prescription lists audit showed a predominance of medicines (drugs) and drug combinations compromised by an increased risk of this serious adverse event. An audit of prescriptions of patients at increased risk of falls as a means of combating polypharmacy and identifying drugs that may cause falls can be conducted using the «Traffic light classification of FRIDs» and drug checkers to identify clinically relevant combinations. The use of these clinical and pharmacological tools can improve the quality and safety of medical care in a hospital setting.В статье представлены результаты анализа данных у пациентов многопрофильного стационара старше 75 лет с сердечно-сосудистыми заболеваниями и коморбидными состояниями. Был проведен анализ фармакотерапии геронтологических пациентов, имеющих несколько факторов риска падения, с точки зрения наличия полипрагмазии и межлекарственных взаимодействий, опасных по риску падения. У группы пациентов, испытавших падение в стационаре по сравнению с пациентами без падения, аудит листов назначений показал преобладание лекарственных средств и их комбинаций, скомпрометированных по повышенному риску этого серьёзного нежелательного явления. Аудит лекарственных назначений пациентам с повышенным риском падений как средство борьбы с полипрагмазией и выявления лекарственных средств, способных вызвать падение, можно проводить с использованием «Светофорной классификации лекарственных средств, повышающих риск падений» и drug-чекера (Drug Interactions Checker интернет-ресурса www.drugs.com) для выявления клинически значимых комбинаций. Использование этих клинико-фармакологических инструментов может способствовать повышению качества и безопасности оказания медицинской помощи в условиях стационара.

Published
2022

12. Kinetic Characterization of SARS-CoV-2 nsp13 ATPase Activity and Discovery of Small-Molecule Inhibitors

Author

Aliakbar Khalili Yazdi, Paknoosh Pakarian, Sumera Perveen, Taraneh Hajian, Vijayaratnam Santhakumar, Albina Bolotokova, Fengling Li, and Masoud Vedadi

Subjects
Adenosine Triphosphatases, Infectious Diseases, SARS-CoV-2, Nucleic Acids, COVID-19, DNA, Single-Stranded, Humans, Methyltransferases, Viral Nonstructural Proteins, RNA Helicases
Abstract

SARS-CoV-2 non-structural protein 13 (nsp13) is a highly conserved helicase and RNA 5'-triphosphatase. It uses the energy derived from the hydrolysis of nucleoside triphosphates for directional movement along the nucleic acids and promotes the unwinding of double-stranded nucleic acids. Nsp13 is essential for replication and propagation of all human and non-human coronaviruses. Combined with its defined nucleotide binding site and druggability, nsp13 is one of the most promising candidates for the development of pan-coronavirus therapeutics. Here, we report the development and optimization of bioluminescence assays for kinetic characterization of nsp13 ATPase activity in the presence and absence of single-stranded DNA. Screening of a library of 5000 small molecules in the presence of single-stranded DNA resulted in the discovery of six nsp13 small-molecule inhibitors with IC

Published
2022

13. Crystal structure of SARS-CoV-2 nsp10-nsp16 in complex with small molecule inhibitors, SS148 and WZ16

Author

Martin Klima, Aliakbar Khalili Yazdi, Fengling Li, Irene Chau, Taraneh Hajian, Albina Bolotokova, H. Ümit Kaniskan, Yulin Han, Ke Wang, Deyao Li, Minkui Luo, Jian Jin, Evzen Boura, and Masoud Vedadi

Subjects
SARS-CoV-2, Humans, RNA, Viral, Methyltransferases, Viral Nonstructural Proteins, Molecular Biology, Biochemistry, COVID-19 Drug Treatment
Abstract

SARS-CoV-2 nsp10-nsp16 complex is a 2'-O-methyltransferase (MTase) involved in viral RNA capping, enabling the virus to evade the immune system in humans. It has been considered a valuable target in the discovery of antiviral therapeutics, as the RNA cap formation is crucial for viral propagation. Through cross-screening of the inhibitors that we previously reported for SARS-CoV-2 nsp14 MTase activity against nsp10-nsp16 complex, we identified two compounds (SS148 and WZ16) that also inhibited nsp16 MTase activity. To further enable the chemical optimization of these two compounds towards more potent and selective dual nsp14/nsp16 MTase inhibitors, we determined the crystal structure of nsp10-nsp16 in complex with each of SS148 and WZ16. As expected, the structures revealed the binding of both compounds to S-adenosyl-L-methionine (SAM) binding pocket of nsp16. However, our structural data along with the biochemical mechanism of action determination revealed an RNA-dependent SAM-competitive pattern of inhibition for WZ16, clearly suggesting that binding of the RNA first may help the binding of some SAM competitive inhibitors. Both compounds also showed some degree of selectivity against human protein MTases, an indication of great potential for chemical optimization towards more potent and selective inhibitors of coronavirus MTases.

Published
2022

14. Crystal structure of SARS‐CoV ‐2 nsp10–nsp16 in complex with small molecule inhibitors, SS148 and WZ16

Author

Klima, Martin, primary, Khalili Yazdi, Aliakbar, additional, Li, Fengling, additional, Chau, Irene, additional, Hajian, Taraneh, additional, Bolotokova, Albina, additional, Kaniskan, H. Ümit, additional, Han, Yulin, additional, Wang, Ke, additional, Li, Deyao, additional, Luo, Minkui, additional, Jin, Jian, additional, Boura, Evzen, additional, and Vedadi, Masoud, additional

Published
2022
Full Text
View/download PDF

17. A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization

Author

Dilworth, David, primary, Hanley, Ronan P., additional, Ferreira de Freitas, Renato, additional, Allali-Hassani, Abdellah, additional, Zhou, Mengqi, additional, Mehta, Naimee, additional, Marunde, Matthew R., additional, Ackloo, Suzanne, additional, Carvalho Machado, Raquel Arminda, additional, Khalili Yazdi, Aliakbar, additional, Owens, Dominic D. G., additional, Vu, Victoria, additional, Nie, David Y., additional, Alqazzaz, Mona, additional, Marcon, Edyta, additional, Li, Fengling, additional, Chau, Irene, additional, Bolotokova, Albina, additional, Qin, Su, additional, Lei, Ming, additional, Liu, Yanli, additional, Szewczyk, Magdalena M., additional, Dong, Aiping, additional, Kazemzadeh, Sina, additional, Abramyan, Tigran, additional, Popova, Irina K., additional, Hall, Nathan W., additional, Meiners, Matthew J., additional, Cheek, Marcus A., additional, Gibson, Elisa, additional, Kireev, Dmitri, additional, Greenblatt, Jack F., additional, Keogh, Michael-C., additional, Min, Jinrong, additional, Brown, Peter J., additional, Vedadi, Masoud, additional, Arrowsmith, Cheryl H., additional, Barsyte-Lovejoy, Dalia, additional, James, Lindsey I., additional, and Schapira, Matthieu, additional

Published
2021
Full Text
View/download PDF

18. CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson’s Disease Associated Protein

Author

Li, Fengling, Ackloo, Suzanne, Arrowsmith, Cheryl H., Ban, Fuqiang, Barden, Christopher J., Beck, Hartmut, Beránek, Jan, Berenger, Francois, Bolotokova, Albina, Bret, Guillaume, Breznik, Marko, Carosati, Emanuele, Chau, Irene, Chen, Yu, Cherkasov, Artem, Corte, Dennis Della, Denzinger, Katrin, Dong, Aiping, Draga, Sorin, Dunn, Ian, Edfeldt, Kristina, Edwards, Aled, Eguida, Merveille, Eisenhuth, Paul, Friedrich, Lukas, Fuerll, Alexander, Gardiner, Spencer S, Gentile, Francesco, Ghiabi, Pegah, Gibson, Elisa, Glavatskikh, Marta, Gorgulla, Christoph, Guenther, Judith, Gunnarsson, Anders, Gusev, Filipp, Gutkin, Evgeny, Halabelian, Levon, Harding, Rachel J., Hillisch, Alexander, Hoffer, Laurent, Hogner, Anders, Houliston, Scott, Irwin, John J, Isayev, Olexandr, Ivanova, Aleksandra, Jacquemard, Celien, Jarrett, Austin J, Jensen, Jan H., Kireev, Dmitri, Kleber, Julian, Koby, S. Benjamin, Koes, David, Kumar, Ashutosh, Kurnikova, Maria G., Kutlushina, Alina, Lessel, Uta, Liessmann, Fabian, Liu, Sijie, Lu, Wei, Meiler, Jens, Mettu, Akhila, Minibaeva, Guzel, Moretti, Rocco, Morris, Connor J, Narangoda, Chamali, Noonan, Theresa, Obendorf, Leon, Pach, Szymon, Pandit, Amit, Perveen, Sumera, Poda, Gennady, Polishchuk, Pavel, Puls, Kristina, Pütter, Vera, Rognan, Didier, Roskams-Edris, Dylan, Schindler, Christina, Sindt, François, Spiwok, Vojtěch, Steinmann, Casper, Stevens, Rick L., Talagayev, Valerij, Tingey, Damon, Vu, Oanh, Walters, W. Patrick, Wang, Xiaowen, Wang, Zhenyu, Wolber, Gerhard, Wolf, Clemens Alexander, Wortmann, Lars, Zeng, Hong, Zepeda, Carlos A., Zhang, Kam Y. J., Zhang, Jixian, Zheng, Shuangjia, and Schapira, Matthieu

Abstract

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson’s disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods. Of the 1955 molecules predicted by participants in Round 1 of the challenge, 73 were found to bind to LRRK2 in an SPR assay with a KDlower than 150 μM. These 73 molecules were advanced to the Round 2 hit expansion phase, where computational teams each selected up to 50 analogs. Binding was observed in two orthogonal assays for seven chemically diverse series, with affinities ranging from 18 to 140 μM. The seven successful computational workflows varied in their screening strategies and techniques. Three used molecular dynamics to produce a conformational ensemble of the targeted site, three included a fragment docking step, three implemented a generative design strategy and five used one or more deep learning steps. CACHE #1 reflects a highly exploratory phase in computational drug design where participants adopted strikingly diverging screening strategies. Machine learning-accelerated methods achieved similar results to brute force (e.g., exhaustive) docking. First-in-class, experimentally confirmed compounds were rare and weakly potent, indicating that recent advances are not sufficient to effectively address challenging targets.

Published
2024
Full Text
View/download PDF

19. A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins

Author

Ackloo, Suzanne, Li, Fengling, Szewczyk, Magda, Seitova, Almagul, Loppnau, Peter, Zeng, Hong, Xu, Jin, Ahmad, Shabbir, Arnautova, Yelena A, Baghaie, A. J., Beldar, Serap, Bolotokova, Albina, Centrella, Paolo A., Chau, Irene, Clark, Matthew A., Cuozzo, John W., Dehghani-Tafti, Saba, Disch, Jeremy S., Dong, Aiping, Dumas, Antoine, Feng, Jianwen A., Ghiabi, Pegah, Gibson, Elisa, Gilmer, Justin, Goldman, Brian, Green, Stuart R, Guié, Marie-Aude, Guilinger, John P., Harms, Nathan, Herasymenko, Oleksandra, Houliston, Scott, Hutchinson, Ashley, Kearnes, Steven, Keefe, Anthony D., Kimani, Serah W., Kramer, Trevor, Kutera, Maria, Kwak, Haejin A., Lento, Cristina, Li, Yanjun, Liu, Jenny, Loup, Joachim, Machado, Raquel A. C., Mulhern, Christopher J., Perveen, Sumera, Righetto, Germanna L., Riley, Patrick, Shrestha, Suman, Sigel, Eric A., Silva, Madhushika, Sintchak, Michael D., Slakman, Belinda L., Taylor, Rhys D., Thompson, James, Torng, Wen, Underkoffler, Carl, von Rechenberg, Moritz, Walsh, Ryan T., Watson, Ian, Wilson, Derek J., Wolf, Esther, Yadav, Manisha, Yazdi, Aliakbar K., Zhang, Junyi, Zhang, Ying, Santhakumar, Vijayaratnam, Edwards, Aled M., Barsyte-Lovejoy, Dalia, Schapira, Matthieu, Brown, Peter J., Halabelian, Levon, and Arrowsmith, Cheryl H.

Abstract

Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) to predict ligands from virtual libraries yielded first-in-class, drug-like ligands for 7 of the 16 WDR domains screened, thus demonstrating the broader ligandability of WDRs. This study establishes a template for evaluation of protein family wide ligandability and provides an extensive resource of WDR protein biochemical and chemical tools, knowledge, and protocols to discover potential therapeutics for this highly disease-relevant, but underexplored target class.

Published
2024
Full Text
View/download PDF

20. Subpocket Similarity-Based Hit Identification for Challenging Targets: Application to the WDR Domain of LRRK2

Author

Eguida, Merveille, Bret, Guillaume, Sindt, François, Li, Fengling, Chau, Irene, Ackloo, Suzanne, Arrowsmith, Cheryl, Bolotokova, Albina, Ghiabi, Pegah, Gibson, Elisa, Halabelian, Levon, Houliston, Scott, Harding, Rachel J., Hutchinson, Ashley, Loppnau, Peter, Perveen, Sumera, Seitova, Almagul, Zeng, Hong, Schapira, Matthieu, and Rognan, Didier

Abstract

We herewith applied a prioria generic hit identification method (POEM) for difficult targets of known three-dimensional structure, relying on the simple knowledge of physicochemical and topological properties of a user-selected cavity. Searching for local similarity to a set of fragment-bound protein microenvironments of known structure, a point cloud registration algorithm is first applied to align known subpockets to the target cavity. The resulting alignment then permits us to directly pose the corresponding seed fragments in a target cavity space not typically amenable to classical docking approaches. Last, linking potentially connectable atoms by a deep generative linker enables full ligand enumeration. When applied to the WD40 repeat (WDR) central cavity of leucine-rich repeat kinase 2 (LRRK2), an unprecedented binding site, POEM was able to quickly propose 94 potential hits, five of which were subsequently confirmed to bind in vitroto LRRK2-WDR.

Published
2024
Full Text
View/download PDF

21. [Polypragmasia and interdrug interactions as risk factors of falling in elderly patients.]

Author

Ilyina ES, Shalygin VA, Bogova OT, Potapov VN, Bolotokova AV, Savelyeva MI, Sinitsina II, Doskina EV, and Sychev DA

Subjects
Humans, Aged, Risk Factors, Accidental Falls prevention & control, Polypharmacy
Abstract

This article presents the results of the analysis of data from patients over 75 years of age from a multidisciplinary hospital with cardiovascular disease and comorbid conditions. Pharmacotherapy of gerontological patients with multiple risk factors for falls was analysed in terms of the presence of polypragmasy and drug-drug interactions hazardous to the risk of falls. In the group of patients who experienced a fall in hospital compared to patients without a fall, the prescription lists audit showed a predominance of medicines (drugs) and drug combinations compromised by an increased risk of this serious adverse event. An audit of prescriptions of patients at increased risk of falls as a means of combating polypharmacy and identifying drugs that may cause falls can be conducted using the «Traffic light classification of FRIDs» and drug checkers to identify clinically relevant combinations. The use of these clinical and pharmacological tools can improve the quality and safety of medical care in a hospital setting.

Published
2022

Catalog

Books, media, physical & digital resources
See catalog results