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1. Computationally driven discovery of SARS-CoV-2 Mpro inhibitors: from design to experimental validation

Author

Khoury, L. El, Jing, Z., Cuzzolin, A., Deplano, A., Loco, D., Sattarov, B., Hédin, F., Wendeborn, S., Ho, C., Ahdab, D. El, Inizan, T. Jaffrelot, Sturlese, M., Sosic, A., Volpiana, M., Lugato, A., Barone, M., Gatto, B., Macchia, M. Ludovica, Bellanda, M., Battistutta, R., Salata, C., Kondratov, I., Iminov, R., Khairulin, A., Mykhalonok, Y., Pochepko, A., Chashka-Ratushnyi, V., Kos, I., Moro, S., Montes, M., Ren, P., Ponder, J. W., Lagardère, L., Piquemal, J. -P., and Sabbadin, D.

Subjects
Physics - Chemical Physics, Quantitative Biology - Biomolecules
Abstract

We report a fast-track computationally-driven discovery of new SARS-CoV2 Main Protease (M$^{pro}$) inhibitors whose potency range from mM for initial non-covalent ligands to sub-$\mu$M for the final covalent compound (IC50=830 +/- 50 nM). The project extensively relied on high-resolution all-atom molecular dynamics simulations and absolute binding free energy calculations performed using the polarizable AMOEBA force field. The study is complemented by extensive adaptive sampling simulations that are used to rationalize the different ligands binding poses through the explicit reconstruction of the ligand-protein conformation spaces. Machine Learning predictions are also performed to predict selected compound properties. While simulations extensively use High Performance Computing to strongly reduce time-to-solution, they were systematically coupled to Nuclear Magnetic Resonance experiments to drive synthesis and to in vitro characterization of compounds. Such study highlights the power of in silico strategies that rely on structure-based approaches for drug design and allows to address the protein conformational multiplicity problem. The proposed fluorinated tetrahydroquinolines open routes for further optimization of M$^{pro}$ inhibitors towards low nM affinities.

Published
2021
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2. Decarbonizzare l'immaginario culturale

Author

Acanfora, M., Ruggieriu, G., Caserini S., Giannelli E., Corrado A., Aneris V., Monforti F., Savaresi A., Tricarico A., Pileri P., Grassi G., Bocci R., Carrosio G., Agazzi D., Sarfatti C., Realini A., Bertello A., Cacciari P., Volpi A., Baranes A., Sabbadin D., De Luca E., Mancini R., Soletti C., Deriu M., Gesualdi F., Ruggieri, G, Van Aken, M, Acanfora, M., Ruggieriu, G., Caserini S., Giannelli E., Corrado A., Aneris V., Monforti F., Savaresi A., Tricarico A., Pileri P., Grassi G., Bocci R., Carrosio G., Agazzi D., Sarfatti C., Realini A., Bertello A., Cacciari P., Volpi A., Baranes A., Sabbadin D., De Luca E., Mancini R., Soletti C., Deriu M., Gesualdi F., Ruggieri, G, and Van Aken, M

Abstract

Il linguaggio scientifico e il senso comune nell’affrontare la crisi ambientale vive di metafore, ma anche di una tragica assenza di cornici ambientali per parlare di relazioni, e non solo tra umani. Se il nostro modello è fondato sulla chiara dicotomia tra cultura e natura, esso mostra la difficoltà a cogliere le dinamiche della realtà che sbaragliano continuamente i cassetti ben ordinati, separati, tra soggetti di natura e soggetti della cultura. Come insegna il glaciologo Lorius: “e dunque il giorno in cui cambiamo lo sguardo, dobbiamo cambiare il vocabolario. Il giorno in cui cambia il mondo, bisogna cambiare i nomi” (2010:13). E perciò partiamo da tre metafore per iniziare a compostare il nostro immaginario.

Published
2021

3. Estudo do efeito do desalinhamento da máscara de porta sobre a corrente de dreno em MOSFETs com geometria de porta trapezoidal

Author

Sabbadin, D. S. and Giacomini, R.

Subjects
Porta trapezoidal, Transistores
Abstract

Este trabalho trata do estudo do efeito do desalinhamento da máscara de porta sobre as características elétricas dos MOSFETs (Metal Oxide Semiconductor Field Effect Transistor), com formato de portas não retangulares. Para a parte experimental, alguns protótipos foram manufaturados em tecnologia CMOS, utilizando-se o programa educacional multiusuário de fabricação de circuitos integrados do MOSIS. A estrutura de teste triangular desalinhada é um arranjo de MOSFETs, com portas não retangulares, utilizável para extração do desalinhamento entre a porta do MOSFET e as demais estruturas, em função das diferenças de corrente de dreno. Embora tais estruturas tenham formatos não retangulares, que podem ser inadequados ao projeto de circuitos convencionais, a vantagem de se medir corrente em relação à tensão, as fazem muito úteis. Este trabalho foi executado em três etapas. Na primeira etapa foram simuladas estruturas tridimensionais em tecnologia Convencional (Bulk) e SOI (Silicon On Insulator) mantendo-se a largura de canal dos MOSFETs constante e variando-se os desalinhamentos de porta na faixa de 0 nm a 250 nm. Na segunda etapa foram simuladas estruturas Convencionais (Bulk) e SOI (Silicon On Insulator), com as medidas reais construídas pela tecnologia oferecida pelo programa de pesquisa do MOSIS, variando-se a largura de canal dos MOSFETs e deslocando a porta na faixa de 0 nm a 490 nm. Na terceira e última etapa foram realizadas medidas experimentais em 30 dispositivos de portas trapezoidais com dois drenos distintos e fonte em comum. Um modelo algébrico para cálculo de desalinhamento foi estudado e aferido a partir das medidas e simulações. Como resultado das simulações e medições constatou-se a precisão do modelo de desalinhamento estudado em ambas as tecnologias, Convencional (Bulk) e SOI (Silicon On Insulator). This work deals with the study of the effect of gate mask misalignment on the electrical characteristics of the MOSFETs (Metal-Oxide-Semiconductor Field Effect Transistor) structures with non-rectangular gate shapes. For the experimental part, some prototypes were manufactured of CMOS technology in educational multi-user manufacture program of integrated circuits MOSIS. The misaligned triangular test structure is an arrangement of MOSFETs with non-rectangular gates, usable for extraction of misalignment between gate and the other MOSFET structures, as a function of the differences in drain current. Although such structures have non-rectangular shapes, which may be unsuitable to the conventional circuit design, the advantage of measuring current over-voltage, make them very useful. This work was performed in three steps. In the first step were simulated three-dimensional structures in conventional technology (Bulk) and SOI (Silicon On Insulator) maintaining the channel width of MOSFETs constant and varying the gate misalignment in the range of 0 nm to 250 nm. In the second step were simulated conventional structures (Bulk) and SOI (Silicon On Insulator) with the actual measures constructed by the technology offered by MOSIS, varying the channel width of the MOSFETs and shifting the gate in the range of 0 nm to 490 nm. In the third and final step, experimental measurements were performed on 30 trapezoidal gates devices with two distinct drains and common source. An algebraic model for calculation of misalignment was studied and benchmarked from measurements and simulations. As a result of the simulations and measurements, were confirmed the accuracy of the misalignment model studied in both technologies, conventional (Bulk) and SOI (Silicon On Insulator).

Published
2014

4. The additional value of patient-reported health status in predicting 1-year mortality after invasive coronary procedures: a report from the Euro Heart Survey on Coronary Revascularisation

Author

Lenzen M. J., Scholte Op Reimer W. J. M., Pedersen S. S., Boersma E., Maier W., Widimsky P., Simoons M. L., Mercado N. F., Wijns W., Bertrand M., Meier B., Sechtem U., Sergeant P., Stahle E., Unger F., Manini M., Bramley C., Laforest V., Taylor C., Del Gaiso S., Huber K., De Backer G., Sirakova V., Cerbak R., Thayssen P., Lehto S., Blanc J. -J., Delahaye F., Kobulia B., Zeymer U., Cokkinos D., Karlocai K., Graham I., Shelley E., Behar S., Maggioni A., Grabauskiene V., Deckers J., Asmussen I., Stepinska J., Goncalves L., Mareev V., Riecansky I., Kenda M. F., Alonso A., Lopez-Sendon J. L., Rosengren A., Buser P., Okay T., Sychov O., Fox K., Wood D., Crijns H., McGregor K., Mulder B., Priori S., Ryden L., Tavazzi L., Vahanian A., Vardas P., Sarkisyan K., Glogar H. D., Frick M., Pachinger O., Zwick R., Vrints C., Van Hertbruggen E., Vercammen M., Sysmans T., Schroeder E., Domange J., De Pril H., De Vriese J., Van Hecke T., Legrand V., Gillon M. -F., Richardy M., Doneux P., Petrov I., Jorgova J., Starcevic B., Eeckhout E., Berger A., Prudent V., Camenzind E., Masson N., Zambartas C., Kleanthous H., Stellova B., Aschermann M., Simek S., Kautzner J., Karmazin V., Svab P., Indrak J., Branny M., Hladilova K., Kala P., Cappelen H., Jensen L. O., Gitt A., Gehrke K., am Rhein L., Erbel R., Gutersohn A., Eggebrecht H., Al Khani M., Rosenberger A., Vogelsberg H., Klepzig H., Schmidt A., Silber S., Mau B., Leuner C., Czyborra K., Reuschling C., Muno E., Nauheim B., Kleber F., Rux S., Saad A., Elabady M., Beiras A. C., Fernandez J. S., del Arno F. N., Romo A. I., Fernandez J. M. C., Mayoreal A. R., Rebanal F. J. R., de la Borbolla M. G., Chaparro M., Brotons C., Miralda C. P., Vila i Perez S. I., Moris C., Aviles F. F., de la Fuente Galan L., Vinuela P. T., de Torres F. M., Mora J., Rodriguez I. S., Bustamante I. P., Fernandez P. L. S., Torrent J. L. D., Diez Gil J. L., Perpinan J., Motilla V. P., Juango M. S. A., Berjon-Reyero J., Moreno R. M., Guerrero J. C. F., Savolainen K., Syvanne M., Cohen-Solal A., Oboa A. -S., Bassand J. P., Espinosa D. P., Jouet V., Cedex B., Montalescot G., Gallois V., Daubert J. C., Clerc J. M., Machecourt J., Cottin Y., Walker D., Holland F., Prosser J., Muir L., Barber K., Cleland J. G. F., Cook J., Chapichadze Z., Christos I. S. A., Tsiavou N., Chrysohoou C., Manginas A., Terrovitis J., Kanakakis J., Vavuranakis M., Drakos S., Farmakis T., Samara C., Papakosta C., Bourantas C., Michalis L. K., Christos M., Foussas S., Adamopoulou E., Vardas P. E., Marketou M., Alotti N., Basa A. M., Vigh A., Preda I., Csoti E., Keltai M., Kerkovits G., Hendler A., Blatt A., Yakov B., Beyar R., Shefer A., Halon D., Bentzvi M., Avramovitch N., Bakst A., Saba K., Cafri C., Grosbard A., Sheva B., Margolis B., Suleiman K., Banai S., Meerkin D., Mosseri M., Guita P., Jabara R., Jafari J., Shitrit D. B., Ghasan Salameh, Brezins M., van den Akker-Berman L., Guetta V., Hashomer T., Rozenman Y., Biagini A., Berti S., Ferrero M., Colombo A., Roccaforte R., Milici C., Scarpino L., Salvi A., Desideri A., Sabbadin D., Veneto C., Galassi A., Giuffrida G., Rognoni A., Vassanelli C., Paffoni P., Cioppa A., Rubino P., de Carlo M., Petronio A. S., Naccarella F., Saia F., Marzocchi A., Maranga S. S., Presbitero P., Valsecchi F., Piscione F., Esposito G., Santini N. M., Tubaro M., Erglis A., Narbute I., Kavoliuniene A., Zaliunas R., Navickas R., Luckute D., Subkovas E., Wagner D., Vermeer F., Lousberg A., Fransen H., Breeman A., Tebbe H., De Boer M. J., van der Wal M., Vos J., Leenders C. M., Veerhoek M. J., Jansen C., Bijl M., Koppelaar C., den Linden V., Brons R., Widdershofen J. W. M. G., Broers H., Kontny F., Jonzon M., Wodniecki J., Tomasik A., Trusz-Gluza M., Nowak S., Ruzyllo W., Deptuch T., Marques J., Matias F., Madeira H., Oliveira J., Sargento L., Ionac A., Dragulescu I. S., Mut-Vitcu B., Maximov D., Dorobantu M., Apetrei E., Niculescu R., Petrescu V., Bucsa A., Deleanu D., Bucharest, Benedek I. S., Hintea T., Aronov D., Tikhomirova E., Kranjec I., Prokselj K., Kanic V., Sepetoglu A., Aytekin S., Aytekin V., Catakoglu A. B., Parlar H., Tufekcioglu S., Ozyedek Z., Baltali M., Kiziltan D., Vukovic M., Neskovic A. N., Cardiology, Lenzen, M. J., Scholte Op Reimer, W. J. M., Pedersen, S. S., Boersma, E., Maier, W., Widimsky, P., Simoons, M. L., Mercado, N. F., Wijns, W., Bertrand, M., Meier, B., Sechtem, U., Sergeant, P., Stahle, E., Unger, F., Manini, M., Bramley, C., Laforest, V., Taylor, C., Del Gaiso, S., Huber, K., De Backer, G., Sirakova, V., Cerbak, R., Thayssen, P., Lehto, S., Blanc, J. -J., Delahaye, F., Kobulia, B., Zeymer, U., Cokkinos, D., Karlocai, K., Graham, I., Shelley, E., Behar, S., Maggioni, A., Grabauskiene, V., Deckers, J., Asmussen, I., Stepinska, J., Goncalves, L., Mareev, V., Riecansky, I., Kenda, M. F., Alonso, A., Lopez-Sendon, J. L., Rosengren, A., Buser, P., Okay, T., Sychov, O., Fox, K., Wood, D., Crijns, H., Mcgregor, K., Mulder, B., Priori, S., Ryden, L., Tavazzi, L., Vahanian, A., Vardas, P., Sarkisyan, K., Glogar, H. D., Frick, M., Pachinger, O., Zwick, R., Vrints, C., Van Hertbruggen, E., Vercammen, M., Sysmans, T., Schroeder, E., Domange, J., De Pril, H., De Vriese, J., Van Hecke, T., Legrand, V., Gillon, M. -F., Richardy, M., Doneux, P., Petrov, I., Jorgova, J., Starcevic, B., Eeckhout, E., Berger, A., Prudent, V., Camenzind, E., Masson, N., Zambartas, C., Kleanthous, H., Stellova, B., Aschermann, M., Simek, S., Kautzner, J., Karmazin, V., Svab, P., Indrak, J., Branny, M., Hladilova, K., Kala, P., Cappelen, H., Jensen, L. O., Gitt, A., Gehrke, K., am Rhein, L., Erbel, R., Gutersohn, A., Eggebrecht, H., Al Khani, M., Rosenberger, A., Vogelsberg, H., Klepzig, H., Schmidt, A., Silber, S., Mau, B., Leuner, C., Czyborra, K., Reuschling, C., Muno, E., Nauheim, B., Kleber, F., Rux, S., Saad, A., Elabady, M., Beiras, A. C., Fernandez, J. S., del Arno, F. N., Romo, A. I., Fernandez, J. M. C., Mayoreal, A. R., Rebanal, F. J. R., de la Borbolla, M. G., Chaparro, M., Brotons, C., Miralda, C. P., Vila i Perez, S. I., Moris, C., Aviles, F. F., de la Fuente Galan, L., Vinuela, P. T., de Torres, F. M., Mora, J., Rodriguez, I. S., Bustamante, I. P., Fernandez, P. L. S., Torrent, J. L. D., Diez Gil, J. L., Perpinan, J., Motilla, V. P., Juango, M. S. A., Berjon-Reyero, J., Moreno, R. M., Guerrero, J. C. F., Savolainen, K., Syvanne, M., Cohen-Solal, A., Oboa, A. -S., Bassand, J. P., Espinosa, D. P., Jouet, V., Cedex, B., Montalescot, G., Gallois, V., Daubert, J. C., Clerc, J. M., Machecourt, J., Cottin, Y., Walker, D., Holland, F., Prosser, J., Muir, L., Barber, K., Cleland, J. G. F., Cook, J., Chapichadze, Z., Christos, I. S. A., Tsiavou, N., Chrysohoou, C., Manginas, A., Terrovitis, J., Kanakakis, J., Vavuranakis, M., Drakos, S., Farmakis, T., Samara, C., Papakosta, C., Bourantas, C., Michalis, L. K., Christos, M., Foussas, S., Adamopoulou, E., Vardas, P. E., Marketou, M., Alotti, N., Basa, A. M., Vigh, A., Preda, I., Csoti, E., Keltai, M., Kerkovits, G., Hendler, A., Blatt, A., Yakov, B., Beyar, R., Shefer, A., Halon, D., Bentzvi, M., Avramovitch, N., Bakst, A., Saba, K., Cafri, C., Grosbard, A., Sheva, B., Margolis, B., Suleiman, K., Banai, S., Meerkin, D., Mosseri, M., Guita, P., Jabara, R., Jafari, J., Shitrit, D. B., Ghasan, Salameh, Brezins, M., van den Akker-Berman, L., Guetta, V., Hashomer, T., Rozenman, Y., Biagini, A., Berti, S., Ferrero, M., Colombo, A., Roccaforte, R., Milici, C., Scarpino, L., Salvi, A., Desideri, A., Sabbadin, D., Veneto, C., Galassi, A., Giuffrida, G., Rognoni, A., Vassanelli, C., Paffoni, P., Cioppa, A., Rubino, P., de Carlo, M., Petronio, A. S., Naccarella, F., Saia, F., Marzocchi, A., Maranga, S. S., Presbitero, P., Valsecchi, F., Piscione, F., Esposito, G., Santini, N. M., Tubaro, M., Erglis, A., Narbute, I., Kavoliuniene, A., Zaliunas, R., Navickas, R., Luckute, D., Subkovas, E., Wagner, D., Vermeer, F., Lousberg, A., Fransen, H., Breeman, A., Tebbe, H., De Boer, M. J., van der Wal, M., Vos, J., Leenders, C. M., Veerhoek, M. J., Jansen, C., Bijl, M., Koppelaar, C., den Linden, V., Brons, R., Widdershofen, J. W. M. G., Broers, H., Kontny, F., Jonzon, M., Wodniecki, J., Tomasik, A., Trusz-Gluza, M., Nowak, S., Ruzyllo, W., Deptuch, T., Marques, J., Matias, F., Madeira, H., Oliveira, J., Sargento, L., Ionac, A., Dragulescu, I. S., Mut-Vitcu, B., Maximov, D., Dorobantu, M., Apetrei, E., Niculescu, R., Petrescu, V., Bucsa, A., Deleanu, D., Bucharest, Benedek, I. S., Hintea, T., Aronov, D., Tikhomirova, E., Kranjec, I., Prokselj, K., Kanic, V., Sepetoglu, A., Aytekin, S., Aytekin, V., Catakoglu, A. B., Parlar, H., Tufekcioglu, S., Ozyedek, Z., Baltali, M., Kiziltan, D., Vukovic, M., and Neskovic, A. N.

Subjects
Male, medicine.medical_specialty, Epidemiology, medicine.medical_treatment, Health Status, Coronary Artery Disease, Revascularization, Coronary artery disease, Cohort Studies, Risk Factors, Surveys and Questionnaires, medicine, Myocardial Revascularization, Surveys and Questionnaire, Humans, Prospective Studies, Prospective cohort study, Aged, business.industry, Risk Factor, Mortality rate, Confounding, Middle Aged, medicine.disease, Surgery, Europe, Prospective Studie, Treatment Outcome, Emergency medicine, Population study, Female, Cohort Studie, Cardiology and Cardiovascular Medicine, business, Human, Cohort study
Abstract

Objective: Self-perceived health status may be helpful in identifying patients at high risk for adverse outcomes. The Euro Heart Survey on Coronary Revascularization (EHS-CR) provided an opportunity to explore whether impaired health status was a predictor of 1-year mortality in patients with coronary artery disease (CAD) undergoing angiographic procedures. Methods: Data from the EHS-CR that included 5619 patients from 31 member countries of the European Society of Cardiology were used. Inclusion criteria for the current study were completion of a self-report measure of health status, the EuroQol Questionnaire (EQ-5D) at discharge and information on 1-year follow-up, resulting in a study population of 3786 patients. Results: The 1-year mortality was 3.2% (n = 120). Survivors reported fewer problems on the five dimensions of the EQ-5D as compared with non-survivors. A broad range of potential confounders were adjusted for, which reached a p

Published
2006

5. Patients enrolled in coronary intervention trials are not representative of patients in clinical practice: results from the Euro Heart Survey on Coronary Revascularization

Author

Hordijk-Trion M., Lenzen M., Wijns W., De Jaegere P., Simoons M. L., Scholte Op Reimer W. J. M., Bertrand M. E., Mercado N., Boersma E., Maier W., Meier B., Moris C., Piscione F., Sechtem U., Sergeant P., Stahle E., Vos J., Widimsky P., Unger F., Manini M., Bramley C., Laforest V., Taylor C., Del Gaiso S., Huber K., De Backer G., Sirakova V., Cerbak R., Thayssen P., Lehto S., Blanc J. -J., Delahaye F., Kobulia B., Zeymer U., Cokkinos D., Karlocai K., Graham I., Shelley E., Behar S., Maggioni A., Grabauskiene V., Deckers J., Asmussen I., Stepinska J., Goncalves L., Mareev V., Riecansky I., Kenda M. F., Alonso A., Lopez-Sendon J. L., Rosengren A., Buser P., Okay T., Sychov O., Fox K., Wood D., Crijns H., McGregor K., Mulder B., Priori S., Ryden L., Tavazzi L., Vahanian A., Vardas P., Sarkisyan K., Glogar H. D., Frick M., Pachinger O., Zwick R., Vrints C., Van Hertbruggen E., Vercammen M., Sysmans T., Schroeder E., Domange J., De Pril H., De Vriese J., Van Hecke T., Legrand V., Gillon M. -F., Richardy M., Doneux P., Petrov I., Jorgova J., Starcevic B., Eeckhout E., Berger A., Prudent V., Camenzind E., Masson N., Zambartas C., Kleanthous H., Stellova B., Aschermann M., Simek S., Kautzner J., Karmazin V., Svab P., Indrak J., Branny M., Hladilova K., Kala P., Cappelen H., Jensen L. O., Gitt A., Gehrke K., am Rhein L., Erbel R., Gutersohn A., Eggebrecht H., Al Khani M., Rosenberger A., Vogelsberg H., Klepzig H., Schmidt A., Silber S., Mau B., Leuner C., Czyborra K., Reuschling C., Muno E., Nauheim B., Kleber F., Rux S., Saad A., Elabady M., Beiras A. C., Fernandez J. S., del Arno F. N., Romo A. I., Fernandez J. M. C., Mayoreal A. R., Rebanal F. J. R., de la Borbolla M. G., Chaparro M., Brotons C., Miralda C. P., Vila i Perez S. I., Aviles F. F., de la Fuente Galan L., Vinuela P. T., de Torres F. M., Mora J., Rodriguez I. S., Bustamante I. P., Fernandez P. L. S., Torrent J. L. D., Gil J. L. D., Perpinan J., Motilla V. P., Juango M. S. A., Berjon-Reyero J., Moreno R. M., Guerrero J. C. F., Savolainen K., Syvanne M., Cohen-Solal A., Oboa A. -S., Bassand J. P., Espinosa D. P., Jouet V., Cedex B., Montalescot G., Gallois V., Daubert J. C., Clerc J. M., Machecourt J., Cottin Y., Walker D., Holland F., Prosser J., Muir L., Barber K., Cleland J. G. F., Cook J., Chapichadze Z., Christos I. S. A., Tsiavou N., Chrysohoou C., Manginas A., Terrovitis J., Kanakakis J., Vavuranakis M., Drakos S., Farmakis T., Samara C., Papakosta C., Bourantas C., Michalis L. K., Christos M., Foussas S., Adamopoulou E., Marketou M., Alotti N., Basa A. M., Vigh A., Preda I., Csoti E., Keltai M., Kerkovits G., Hendler A., Blatt A., Yakov B., Beyar R., Shefer A., Halon D., Bentzvi M., Avramovitch N., Bakst A., Saba K., Cafri C., Grosbard A., Sheva B., Margolis B., Suleiman K., Banai S., Meerkin D., Mosseri M., Guita P., Jabara R., Jafari J., Shitrit D. B., Ghasan D., Salameh D., Brezins M., van den Akker-Berman L., Guetta V., Hashomer T., Rozenman Y., Biagini A., Berti S., Ferrero M., Colombo A., Roccaforte R., Milici C., Scarpino L., Salvi A., Desideri A., Sabbadin D., Veneto C., Galassi A., Giuffrida G., Rognoni A., Vassanelli C., Paffoni P., Cioppa A., Rubino P., de Carlo M., Petronio A. S., Naccarella F., Saia F., Marzocchi A., Maranga S. S., Presbitero P., Valsecchi F., Esposito G., Santini N. M., Tubaro M., Erglis A., Narbute I., Kavoliuniene A., Zaliunas R., Navickas R., Luckute D., Subkovas E., Wagner D., Vermeer F., Lousberg A., Fransen H., Breeman A., Tebbe H., De Boer M. J., van der Wal M., Leenders C. M., Veerhoek M. J., Jansen C., Bijl M., Koppelaar C., den Linden V., Brons R., Widdershofen J. W. M. G., Broers H., Kontny F., Jonzon M., Wodniecki J., Tomasik A., Trusz-Gluza M., Nowak S., Ruzyllo W., Deptuch T., Marques J., Matias F., Madeira H., Oliveira J., Sargento L., Ionac A., Dragulescu I. S., Mut-Vitcu B., Maximov D., Dorobantu M., Apetrei E., Niculescu R., Petrescu V., Bucsa A., Deleanu D., Bucharest, Benedek I. S., Hintea T., Aronov D., Tikhomirova E., Kranjec I., Prokselj K., Kanic V., Sepetoglu A., Aytekin S., Aytekin V., Catakoglu A. B., Parlar H., Tufekcioglu S., Ozyedek Z., Baltali M., Kiziltan, Vukovic M., Neskovic A. N., Cardiology, Hordijk-Trion, M., Lenzen, M., Wijns, W., De Jaegere, P., Simoons, M. L., Scholte Op Reimer, W. J. M., Bertrand, M. E., Mercado, N., Boersma, E., Maier, W., Meier, B., Moris, C., Piscione, F., Sechtem, U., Sergeant, P., Stahle, E., Vos, J., Widimsky, P., Unger, F., Manini, M., Bramley, C., Laforest, V., Taylor, C., Del Gaiso, S., Huber, K., De Backer, G., Sirakova, V., Cerbak, R., Thayssen, P., Lehto, S., Blanc, J. -J., Delahaye, F., Kobulia, B., Zeymer, U., Cokkinos, D., Karlocai, K., Graham, I., Shelley, E., Behar, S., Maggioni, A., Grabauskiene, V., Deckers, J., Asmussen, I., Stepinska, J., Goncalves, L., Mareev, V., Riecansky, I., Kenda, M. F., Alonso, A., Lopez-Sendon, J. L., Rosengren, A., Buser, P., Okay, T., Sychov, O., Fox, K., Wood, D., Crijns, H., Mcgregor, K., Mulder, B., Priori, S., Ryden, L., Tavazzi, L., Vahanian, A., Vardas, P., Sarkisyan, K., Glogar, H. D., Frick, M., Pachinger, O., Zwick, R., Vrints, C., Van Hertbruggen, E., Vercammen, M., Sysmans, T., Schroeder, E., Domange, J., De Pril, H., De Vriese, J., Van Hecke, T., Legrand, V., Gillon, M. -F., Richardy, M., Doneux, P., Petrov, I., Jorgova, J., Starcevic, B., Eeckhout, E., Berger, A., Prudent, V., Camenzind, E., Masson, N., Zambartas, C., Kleanthous, H., Stellova, B., Aschermann, M., Simek, S., Kautzner, J., Karmazin, V., Svab, P., Indrak, J., Branny, M., Hladilova, K., Kala, P., Cappelen, H., Jensen, L. O., Gitt, A., Gehrke, K., am Rhein, L., Erbel, R., Gutersohn, A., Eggebrecht, H., Al Khani, M., Rosenberger, A., Vogelsberg, H., Klepzig, H., Schmidt, A., Silber, S., Mau, B., Leuner, C., Czyborra, K., Reuschling, C., Muno, E., Nauheim, B., Kleber, F., Rux, S., Saad, A., Elabady, M., Beiras, A. C., Fernandez, J. S., del Arno, F. N., Romo, A. I., Fernandez, J. M. C., Mayoreal, A. R., Rebanal, F. J. R., de la Borbolla, M. G., Chaparro, M., Brotons, C., Miralda, C. P., Vila i Perez, S. I., Aviles, F. F., de la Fuente Galan, L., Vinuela, P. T., de Torres, F. M., Mora, J., Rodriguez, I. S., Bustamante, I. P., Fernandez, P. L. S., Torrent, J. L. D., Gil, J. L. D., Perpinan, J., Motilla, V. P., Juango, M. S. A., Berjon-Reyero, J., Moreno, R. M., Guerrero, J. C. F., Savolainen, K., Syvanne, M., Cohen-Solal, A., Oboa, A. -S., Bassand, J. P., Espinosa, D. P., Jouet, V., Cedex, B., Montalescot, G., Gallois, V., Daubert, J. C., Clerc, J. M., Machecourt, J., Cottin, Y., Walker, D., Holland, F., Prosser, J., Muir, L., Barber, K., Cleland, J. G. F., Cook, J., Chapichadze, Z., Christos, I. S. A., Tsiavou, N., Chrysohoou, C., Manginas, A., Terrovitis, J., Kanakakis, J., Vavuranakis, M., Drakos, S., Farmakis, T., Samara, C., Papakosta, C., Bourantas, C., Michalis, L. K., Christos, M., Foussas, S., Adamopoulou, E., Marketou, M., Alotti, N., Basa, A. M., Vigh, A., Preda, I., Csoti, E., Keltai, M., Kerkovits, G., Hendler, A., Blatt, A., Yakov, B., Beyar, R., Shefer, A., Halon, D., Bentzvi, M., Avramovitch, N., Bakst, A., Saba, K., Cafri, C., Grosbard, A., Sheva, B., Margolis, B., Suleiman, K., Banai, S., Meerkin, D., Mosseri, M., Guita, P., Jabara, R., Jafari, J., Shitrit, D. B., Ghasan, D., Salameh, D., Brezins, M., van den Akker-Berman, L., Guetta, V., Hashomer, T., Rozenman, Y., Biagini, A., Berti, S., Ferrero, M., Colombo, A., Roccaforte, R., Milici, C., Scarpino, L., Salvi, A., Desideri, A., Sabbadin, D., Veneto, C., Galassi, A., Giuffrida, G., Rognoni, A., Vassanelli, C., Paffoni, P., Cioppa, A., Rubino, P., de Carlo, M., Petronio, A. S., Naccarella, F., Saia, F., Marzocchi, A., Maranga, S. S., Presbitero, P., Valsecchi, F., Esposito, G., Santini, N. M., Tubaro, M., Erglis, A., Narbute, I., Kavoliuniene, A., Zaliunas, R., Navickas, R., Luckute, D., Subkovas, E., Wagner, D., Vermeer, F., Lousberg, A., Fransen, H., Breeman, A., Tebbe, H., De Boer, M. J., van der Wal, M., Leenders, C. M., Veerhoek, M. J., Jansen, C., Bijl, M., Koppelaar, C., den Linden, V., Brons, R., Widdershofen, J. W. M. G., Broers, H., Kontny, F., Jonzon, M., Wodniecki, J., Tomasik, A., Trusz-Gluza, M., Nowak, S., Ruzyllo, W., Deptuch, T., Marques, J., Matias, F., Madeira, H., Oliveira, J., Sargento, L., Ionac, A., Dragulescu, I. S., Mut-Vitcu, B., Maximov, D., Dorobantu, M., Apetrei, E., Niculescu, R., Petrescu, V., Bucsa, A., Deleanu, D., Bucharest, Benedek, I. S., Hintea, T., Aronov, D., Tikhomirova, E., Kranjec, I., Prokselj, K., Kanic, V., Sepetoglu, A., Aytekin, S., Aytekin, V., Catakoglu, A. B., Parlar, H., Tufekcioglu, S., Ozyedek, Z., Baltali, M., Kiziltan, Vukovic, M., and Neskovic, A. N.

Subjects
Male, medicine.medical_specialty, Randomization, medicine.medical_treatment, Euro Heart Survey, Coronary Artery Disease, Revascularization, law.invention, Coronary artery disease, Randomized controlled trial, law, Internal medicine, Angioplasty, medicine, Humans, cardiovascular diseases, Angioplasty, Balloon, Coronary, Coronary Artery Bypass, CABG, Aged, Randomized Controlled Trials as Topic, business.industry, Coronary Artery Bypa, Patient Selection, PCI, Health Survey, Middle Aged, medicine.disease, Health Surveys, Surgery, Clinical trial, Stenosis, surgical procedures, operative, Clinical Trials, Phase III as Topic, Conventional PCI, Female, Cardiology and Cardiovascular Medicine, business, Human
Abstract

Aims: Revascularization in patients with coronary artery disease changed over the last two decades, favouring the number of patients treated by means of percutaneous coronary interventions (PCI) when compared with coronary artery bypass grafting (CABG). Many randomized controlled trials (RCTs) have been performed to compare these two competing revascularization techniques. Because of the strict enrolment criteria of RCTs in which highly selected patients are recruited, the applicability of the results may be limited in clinical practice. The current study evaluates to what extent patients in clinical practice were similar to those who participated in RCTs comparing PCI with CABG. Methods and results: Clinical characteristics and 1-year outcome of 4713 patients enrolled in the Euro Heart Survey on Coronary Revascularization were compared with 8647 patients who participated in 14 major RCTs, comparing PCI with CABG. In addition, we analysed which proportion of survey patients would have disqualified for trial participation (n = 3033, 64%), aiming at identifying differences between trial-eligible and trial-ineligible survey patients. In general, important differences were observed between trial participants and survey patients. Patients in clinical practice were older, more often had comorbid conditions, single-vessel disease, and left main stem stenosis when compared with trial participants. Almost identical differences were observed between trial-eligible and trial-ineligible survey patients. In clinical practice, PCI was the treatment of choice, even in patients who were trial-ineligible (46% PCI, 26% CABG, 28% medical). PCI remained the preferred treatment option in patients with multi-vessel disease (57% in trial-eligible and 40% in trial-ineligible patients, respectively, P < 0.001); yet, the risk profile of patients treated by PCI was better than that for patients treated either by CABG or by medical therapy. In the RCTs, there was no mortality difference between PCI and CABG. In clinical practice, however, we observed 1-year unadjusted survival benefit for PCI vs. CABG (2.9 vs. 5.4%, P < 0.001). Survival benefit was only observed in trial-ineligible patients (3.3 vs. 6.2%, P < 0.001). Conclusion: Many patients in clinical practice were not represented in RCTs. Moreover, only 36% of these patients were considered eligible for participating in a trial comparing PCI with CABG. We demonstrated that RCTs included younger patients with a better cardiovascular risk profile when compared with patients in everyday clinical practice. This study highlights the disparity between patients in clinical practice and patients in whom the studies that provide the evidence for treatment guidelines are performed. © The European Society of Cardiology 2006. All rights reserved.

Published
2006

6. Computationally driven discovery of SARS-CoV-2 M pro inhibitors: from design to experimental validation.

Author

El Khoury L, Jing Z, Cuzzolin A, Deplano A, Loco D, Sattarov B, Hédin F, Wendeborn S, Ho C, El Ahdab D, Jaffrelot Inizan T, Sturlese M, Sosic A, Volpiana M, Lugato A, Barone M, Gatto B, Macchia ML, Bellanda M, Battistutta R, Salata C, Kondratov I, Iminov R, Khairulin A, Mykhalonok Y, Pochepko A, Chashka-Ratushnyi V, Kos I, Moro S, Montes M, Ren P, Ponder JW, Lagardère L, Piquemal JP, and Sabbadin D

Abstract

We report a fast-track computationally driven discovery of new SARS-CoV-2 main protease (M pro ) inhibitors whose potency ranges from mM for the initial non-covalent ligands to sub-μM for the final covalent compound (IC 50 = 830 ± 50 nM). The project extensively relied on high-resolution all-atom molecular dynamics simulations and absolute binding free energy calculations performed using the polarizable AMOEBA force field. The study is complemented by extensive adaptive sampling simulations that are used to rationalize the different ligand binding poses through the explicit reconstruction of the ligand-protein conformation space. Machine learning predictions are also performed to predict selected compound properties. While simulations extensively use high performance computing to strongly reduce the time-to-solution, they were systematically coupled to nuclear magnetic resonance experiments to drive synthesis and for in vitro characterization of compounds. Such a study highlights the power of in silico strategies that rely on structure-based approaches for drug design and allows the protein conformational multiplicity problem to be addressed. The proposed fluorinated tetrahydroquinolines open routes for further optimization of M pro inhibitors towards low nM affinities., Competing Interests: P. R., M. M., L. L., J. W. P. and J.-P. P. are co-founders and shareholders of Qubit Pharmaceuticals., (This journal is © The Royal Society of Chemistry.)

Published
2022
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7. Insecticidal spider toxins are high affinity positive allosteric modulators of the nicotinic acetylcholine receptor.

Author

Chambers C, Cutler P, Huang YH, Goodchild JA, Blythe J, Wang CK, Bigot A, Kaas Q, Craik DJ, Sabbadin D, and Earley FG

Subjects
Allosteric Regulation, Animals, Humans, Insecticides chemistry, Spider Venoms chemistry, Structure-Activity Relationship, Insecticides toxicity, Receptors, Nicotinic drug effects, Spider Venoms toxicity
Abstract

The insecticidal effects of ω-hexatoxin-Hv1a, κ-hexatoxin-Hv1c and ω/κ-hexatoxin-Hv1h are currently attributed to action at calcium and potassium channels. By characterizing the binding of these toxins to neuronal membranes, we show that they have more potent effects as positive allosteric modulators (PAMs) of insect nicotinic acetylcholine receptors (nAChRs), consistent with their neuroexcitatory toxicology. Alanine scanning analysis of ω-hexatoxin-Hv1a reveals a structure-activity relationship for binding that mirrors that for insecticidal activity. Spinosyn A does not compete with ω-hexatoxin-Hv-1a for binding, and we show that these two PAMs have distinct pharmacology of binding indicating that they act at different receptor populations. These toxins represent valuable tools for the characterization of insect nAChRs and for the development of more selective agrochemicals., (© 2019 Federation of European Biochemical Societies.)

Published
2019
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8. Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information.

Author

Paoletta S, Sabbadin D, von Kügelgen I, Hinz S, Katritch V, Hoffmann K, Abdelrahman A, Straßburger J, Baqi Y, Zhao Q, Stevens RC, Moro S, Müller CE, and Jacobson KA

Subjects
Anthraquinones chemistry, Anthraquinones metabolism, Crystallography, X-Ray, Humans, Ligands, Models, Molecular, Molecular Dynamics Simulation, Nucleotides chemistry, Nucleotides metabolism, Protein Conformation, Purinergic P2Y Receptor Agonists metabolism, Purinergic P2Y Receptor Antagonists metabolism, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides metabolism, Molecular Docking Simulation methods, Purinergic P2Y Receptor Agonists chemistry, Purinergic P2Y Receptor Antagonists chemistry, Receptors, Purinergic P2Y12 chemistry, Receptors, Purinergic P2Y12 metabolism
Abstract

The G protein-coupled P2Y12 receptor (P2Y12R) is an important antithrombotic target and of great interest for pharmaceutical discovery. Its recently solved, highly divergent crystallographic structures in complex either with nucleotides (full or partial agonist) or with a nonnucleotide antagonist raise the question of which structure is more useful to understand ligand recognition. Therefore, we performed extensive molecular modeling studies based on these structures and mutagenesis, to predict the binding modes of major classes of P2Y12R ligands previously reported. Various nucleotide derivatives docked readily to the agonist-bound P2Y12R, but uncharged nucleotide-like antagonist ticagrelor required a hybrid receptor resembling the agonist-bound P2Y12R except for the top portion of TM6. Supervised molecular dynamics (SuMD) of ticagrelor binding indicated interactions with the extracellular regions of P2Y12R, defining possible meta-binding sites. Ureas, sulfonylureas, sulfonamides, anthraquinones and glutamic acid piperazines docked readily to the antagonist-bound P2Y12R. Docking dinucleotides at both agonist- and antagonist-bound structures suggested interactions with two P2Y12R pockets. Thus, our structure-based approach consistently rationalized the main structure-activity relationships within each ligand class, giving useful information for designing improved ligands.

Published
2015
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9. The xylanase inhibitor TAXI-III counteracts the necrotic activity of a Fusarium graminearum xylanase in vitro and in durum wheat transgenic plants.

Author

Moscetti I, Faoro F, Moro S, Sabbadin D, Sella L, Favaron F, and D'Ovidio R

Subjects
Enzyme Inhibitors chemistry, Models, Molecular, Molecular Sequence Data, Endo-1,4-beta Xylanases antagonists & inhibitors, Enzyme Inhibitors pharmacology, Fusarium enzymology, Plants, Genetically Modified microbiology, Triticum microbiology
Abstract

The xylanase inhibitor TAXI-III has been proven to delay Fusarium head blight (FHB) symptoms caused by Fusarium graminearum in transgenic durum wheat plants. To elucidate the molecular mechanism underlying the capacity of the TAXI-III transgenic plants to limit FHB symptoms, we treated wheat tissues with the xylanase FGSG&#95;03624, hitherto shown to induce cell death and hydrogen peroxide accumulation. Experiments performed on lemmas of flowering wheat spikes and wheat cell suspension cultures demonstrated that pre-incubation of xylanase FGSG&#95;03624 with TAXI-III significantly decreased cell death. Most interestingly, a reduced cell death relative to control non-transgenic plants was also obtained by treating, with the same xylanase, lemmas of TAXI-III transgenic plants. Molecular modelling studies predicted an interaction between the TAXI-III residue H395 and residues E122 and E214 belonging to the active site of xylanase FGSG&#95;03624. These results provide, for the first time, clear indications in vitro and in planta that a xylanase inhibitor can prevent the necrotic activity of a xylanase, and suggest that the reduced FHB symptoms on transgenic TAXI-III plants may be a result not only of the direct inhibition of xylanase activity secreted by the pathogen, but also of the capacity of TAXI-III to avoid host cell death., (© 2014 BSPP AND JOHN WILEY & SONS LTD.)

Published
2015
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10. Implementing the "Best Template Searching" tool into Adenosiland platform.

Author

Floris M, Sabbadin D, Ciancetta A, Medda R, Cuzzolin A, and Moro S

Abstract

Background: Adenosine receptors (ARs) belong to the G protein-coupled receptors (GCPRs) family. The recent release of X-ray structures of the human A2A AR (h A2A AR ) in complex with agonists and antagonists has increased the application of structure-based drug design approaches to this class of receptors. Among them, homology modeling represents the method of choice to gather structural information on the other receptor subtypes, namely A1, A2B, and A3 ARs. With the aim of helping users in the selection of either a template to build its own models or ARs homology models publicly available on our platform, we implemented our web-resource dedicated to ARs, Adenosiland, with the "Best Template Searching" facility. This tool is freely accessible at the following web address: http://mms.dsfarm.unipd.it/Adenosiland/ligand.php., Findings: The template suggestions and homology models provided by the "Best Template Searching" tool are guided by the similarity of a query structure (putative or known ARs ligand) with all ligands co-crystallized with hA2A AR subtype. The tool computes several similarity indexes and sort the outcoming results according to the index selected by the user., Conclusions: We have implemented our web-resource dedicated to ARs Adenosiland with the "Best Template Searching" facility, a tool to guide template and models selection for hARs modelling. The underlying idea of our new facility, that is the selection of a template (or models built upon a template) whose co-crystallized ligand shares the highest similarity with the query structure, can be easily extended to other GPCRs.

Published
2013
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11. The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit.

Author

Raffaello A, De Stefani D, Sabbadin D, Teardo E, Merli G, Picard A, Checchetto V, Moro S, Szabò I, and Rizzuto R

Subjects
Amino Acid Sequence, Animals, Base Sequence, Calcium Channels genetics, Fluorescence Resonance Energy Transfer, HeLa Cells, Homeostasis, Humans, Lipid Bilayers, Membrane Potential, Mitochondrial, Mice, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Structure, Tertiary, Protein Subunits, Calcium metabolism, Calcium Channels chemistry, Calcium Channels metabolism
Abstract

Mitochondrial calcium uniporter (MCU) channel is responsible for Ruthenium Red-sensitive mitochondrial calcium uptake. Here, we demonstrate MCU oligomerization by immunoprecipitation and Förster resonance energy transfer (FRET) and characterize a novel protein (MCUb) with two predicted transmembrane domains, 50% sequence similarity and a different expression profile from MCU. Based on computational modelling, MCUb includes critical amino-acid substitutions in the pore region and indeed MCUb does not form a calcium-permeable channel in planar lipid bilayers. In HeLa cells, MCUb is inserted into the oligomer and exerts a dominant-negative effect, reducing the [Ca(2+)]mt increases evoked by agonist stimulation. Accordingly, in vitro co-expression of MCUb with MCU drastically reduces the probability of observing channel activity in planar lipid bilayer experiments. These data unveil the structural complexity of MCU and demonstrate a novel regulatory mechanism, based on the inclusion of dominant-negative subunits in a multimeric channel, that underlies the fine control of the physiologically and pathologically relevant process of mitochondrial calcium homeostasis.

Published
2013
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12. Predischarge exercise electrocardiogram and stress echocardiography can predict long-term clinically driven revascularization following acute myocardial infarction.

Author

Desideri A, Bigi R, Cortigiani L, Rambaldi R, Sabbadin D, Curti G, and Celegon L

Subjects
Aged, Angioplasty, Balloon, Coronary, Coronary Artery Bypass, Dipyridamole, Electrocardiography, Exercise Test, Female, Humans, Male, Middle Aged, Prognosis, Risk Assessment, Vasodilator Agents, Echocardiography, Stress, Myocardial Infarction therapy, Myocardial Revascularization
Abstract

Background: Predischarge stress testing provides suboptimal prediction of spontaneous hard events following uncomplicated acute myocardial infarction (AMI)., Hypothesis: This study was aimed at assessing whether soft cardiac ischemic events requiring late revascularization could be predicted more accurately., Methods: In all, 428 patients undergoing exercise electrocardiography (ECG) and stress echocardiography (SE, 345 dobutamine and 83 dypiridamole) within 15 days of uncomplicated AMI were followed up for 425 (range 20-2220) days. Soft ischemic events (effort angina>class II [Canadian Cardiovascular Society Classification] and unstable angina) driving late (>6 months) revascularization were regarded as endpoints., Results: A total of 58 events (29 effort and 29 unstable angina with subsequent 47 coronary artery bypass grafts and 11 percutaneous transluminal coronary angioplasties) occurred: 26 in patients with positive exercise ECG and 34 in patients with positive SE. Univariate predictors of revascularizations were positive exercise ECG (p = 0.0001), peak wall motion score index (WMSI) (p = 0.0009), low workload (p = 0.0018), rest WMSI (p = 0.02) and positive SE (p = 0.02). Cox multivariate analysis selected peak WMSI, positive exercise ECG, and low workload positive exercise ECG as independent predictors of late revascularizations., Conclusions: Predischarge stress testing identifies the long-term occurrence of soft ischemic events driving late revascularization after uncomplicated AMI.

Published
2003
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