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1. Tunable and Portable Extreme-Scale Drug Discovery Platform at Exascale: the LIGATE Approach

Author

Palermo, Gianluca, Accordi, Gianmarco, Gadioli, Davide, Vitali, Emanuele, Silvano, Cristina, Guindani, Bruno, Ardagna, Danilo, Beccari, Andrea R., Bonanni, Domenico, Talarico, Carmine, Lunghini, Filippo, Martinovic, Jan, Silva, Paulo, Bohm, Ada, Beranek, Jakub, Krenek, Jan, Jansik, Branislav, Crisci, Luigi, Biagio, Cosenza, Thoman, Peter, Salzmann, Philip, Fahringer, Thomas, Alexander, Leila, Tauriello, Gerardo, Schwede, Torsten, Durairaj, Janani, Emerson, Andrew, Ficarelli, Federico, Wingbermuhle, Sebastian, Lindahl, Eric, Gregori, Daniele, Sana, Emanuele, Coletti, Silvano, and Gschwandtner, Philip

Subjects
Computer Science - Distributed, Parallel, and Cluster Computing
Abstract

Today digital revolution is having a dramatic impact on the pharmaceutical industry and the entire healthcare system. The implementation of machine learning, extreme-scale computer simulations, and big data analytics in the drug design and development process offers an excellent opportunity to lower the risk of investment and reduce the time to the patient. Within the LIGATE project, we aim to integrate, extend, and co-design best-in-class European components to design Computer-Aided Drug Design (CADD) solutions exploiting today's high-end supercomputers and tomorrow's Exascale resources, fostering European competitiveness in the field. The proposed LIGATE solution is a fully integrated workflow that enables to deliver the result of a virtual screening campaign for drug discovery with the highest speed along with the highest accuracy. The full automation of the solution and the possibility to run it on multiple supercomputing centers at once permit to run an extreme scale in silico drug discovery campaign in few days to respond promptly for example to a worldwide pandemic crisis., Comment: Paper Accepted to the 20th ACM International Conference on Computing Frontiers (CF'23)

Published
2023
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2. GENEOnet: A new machine learning paradigm based on Group Equivariant Non-Expansive Operators. An application to protein pocket detection

Author

Bocchi, Giovanni, Frosini, Patrizio, Micheletti, Alessandra, Pedretti, Alessandro, Gratteri, Carmen, Lunghini, Filippo, Beccari, Andrea Rosario, and Talarico, Carmine

Subjects
Quantitative Biology - Biomolecules, Computer Science - Artificial Intelligence, Computer Science - Machine Learning, Mathematics - Optimization and Control
Abstract

Nowadays there is a big spotlight cast on the development of techniques of explainable machine learning. Here we introduce a new computational paradigm based on Group Equivariant Non-Expansive Operators, that can be regarded as the product of a rising mathematical theory of information-processing observers. This approach, that can be adjusted to different situations, may have many advantages over other common tools, like Neural Networks, such as: knowledge injection and information engineering, selection of relevant features, small number of parameters and higher transparency. We chose to test our method, called GENEOnet, on a key problem in drug design: detecting pockets on the surface of proteins that can host ligands. Experimental results confirmed that our method works well even with a quite small training set, providing thus a great computational advantage, while the final comparison with other state-of-the-art methods shows that GENEOnet provides better or comparable results in terms of accuracy.

Published
2022

3. EXSCALATE: An extreme-scale in-silico virtual screening platform to evaluate 1 trillion compounds in 60 hours on 81 PFLOPS supercomputers

Author

Gadioli, Davide, Vitali, Emanuele, Ficarelli, Federico, Latini, Chiara, Manelfi, Candida, Talarico, Carmine, Silvano, Cristina, Cavazzoni, Carlo, Palermo, Gianluca, and Beccari, Andrea Rosario

Subjects
Computer Science - Distributed, Parallel, and Cluster Computing, Computer Science - Computational Engineering, Finance, and Science
Abstract

The social and economic impact of the COVID-19 pandemic demands the reduction of the time required to find a therapeutic cure. In the contest of urgent computing, we re-designed the Exscalate molecular docking platform to benefit from heterogeneous computation nodes and to avoid scaling issues. We deployed the Exscalate platform on two top European supercomputers (CINECA-Marconi100 and ENI-HPC5), with a combined computational power of 81 PFLOPS, to evaluate the interaction between 70 billions of small molecules and 15 binding-sites of 12 viral proteins of Sars-Cov2. The experiment lasted 60 hours and overall it performed a trillion of evaluations.

Published
2021

4. Structure of human TRPM8 channel

Author

Palchevskyi, Sergii, Czarnocki-Cieciura, Mariusz, Vistoli, Giulio, Gervasoni, Silvia, Nowak, Elżbieta, Beccari, Andrea R., Nowotny, Marcin, and Talarico, Carmine

Published
2023
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5. Relevance of Spike/Estrogen Receptor-α interaction for endothelial-based coagulopathy induced by SARS-CoV-2

Author

Barbieri, Silvia Stella, Cattani, Franca, Sandrini, Leonardo, Grillo, Magda Maria, Amendola, Alessandra, Valente, Carmen, Talarico, Carmine, Iaconis, Daniela, Turacchio, Gabriele, Lucariello, Miriam, Lione, Lucia, Salvatori, Erika, Amadio, Patrizia, Garoffolo, Gloria, Maffei, Mariano, Galli, Francesca, Beccari, Andrea Rosario, Sberna, Giuseppe, Marra, Emanuele, Zoppi, Marica, Michaelides, Michael, Roscilli, Giuseppe, Aurisicchio, Luigi, Bertini, Riccardo, Allegretti, Marcello, and Pesce, Maurizio

Published
2023
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8. Diketo acid inhibitors of nsp13 of SARS-CoV-2 block viral replication

Author

Corona, Angela, Madia, Valentina Noemi, De Santis, Riccardo, Manelfi, Candida, Emmolo, Roberta, Ialongo, Davide, Patacchini, Elisa, Messore, Antonella, Amatore, Donatella, Faggioni, Giovanni, Artico, Marco, Iaconis, Daniela, Talarico, Carmine, Di Santo, Roberto, Lista, Florigio, Costi, Roberta, and Tramontano, Enzo

Published
2023
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12. Paclitaxel binds and activates C5aR1: A new potential therapeutic target for the prevention of chemotherapy-induced peripheral neuropathy and hypersensitivity reactions

Author

Brandolini, Laura, d’Angelo, Michele, Novelli, Rubina, Castelli, Vanessa, Giorgio, Cristina, Sirico, Anna, Cocchiaro, Pasquale, D’Egidio, Francesco, Benedetti, Elisabetta, Cristiano, Claudia, Bugatti, Antonella, Ruocco, Anna, Amendola, Pier Giorgio, Talarico, Carmine, Manelfi, Candida, Iaconis, Daniela, Beccari, Andrea, Quadros, Andreza U., Cunha, Thiago M., Caruso, Arnaldo, Russo, Roberto, Cimini, Annamaria, Aramini, Andrea, and Allegretti, Marcello

Published
2022
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13. Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants

Author

Iaconis, Daniela, Bordi, Licia, Matusali, Giulia, Talarico, Carmine, Manelfi, Candida, Cesta, Maria Candida, Zippoli, Mara, Caccuri, Francesca, Bugatti, Antonella, Zani, Alberto, Filippini, Federica, Scorzolini, Laura, Gobbi, Marco, Beeg, Marten, Piotti, Arianna, Montopoli, Monica, Cocetta, Veronica, Bressan, Silvia, Bucci, Enrico M., Caruso, Arnaldo, Nicastri, Emanuele, Allegretti, Marcello, and Beccari, Andrea R.

Published
2022
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17. A community effort in SARS‐CoV‐2 drug discovery

Author

Schimunek, Johannes, primary, Seidl, Philipp, additional, Elez, Katarina, additional, Hempel, Tim, additional, Le, Tuan, additional, Noé, Frank, additional, Olsson, Simon, additional, Raich, Lluís, additional, Winter, Robin, additional, Gokcan, Hatice, additional, Gusev, Filipp, additional, Gutkin, Evgeny M., additional, Isayev, Olexandr, additional, Kurnikova, Maria G., additional, Narangoda, Chamali H., additional, Zubatyuk, Roman, additional, Bosko, Ivan P., additional, Furs, Konstantin V., additional, Karpenko, Anna D., additional, Kornoushenko, Yury V., additional, Shuldau, Mikita, additional, Yushkevich, Artsemi, additional, Benabderrahmane, Mohammed, additional, Bousquet-Melou, Patrick, additional, Bureau, Ronan, additional, Charton, Beatrice, additional, Cirou, Bertrand, additional, Gil, Gérard, additional, Allen, William J., additional, Sirimulla, Suman, additional, Watowich, Stanley, additional, Antonopoulos, Nick, additional, Epitropakis, Nikolaos, additional, Krasoulis, Agamemnon, additional, Pitsikalis, Vassilis, additional, Theodorakis, Stavros, additional, Kozlovskii, Igor, additional, Maliutin, Anton, additional, Medvedev, Alexander, additional, Popov, Petr, additional, Zaretckii, Mark, additional, Eghbal-zadeh, Hamid, additional, Halmich, Christina, additional, Hochreiter, Sepp, additional, Mayr, Andreas, additional, Ruch, Peter, additional, Widrich, Michael, additional, Berenger, Francois, additional, Kumar, Ashutosh, additional, Yamanishi, Yoshihiro, additional, Zhang, Kam, additional, Bengio, Emmanuel, additional, Bengio, Yoshua, additional, Jain, Moksh, additional, Korablyov, Maksym, additional, Liu, Cheng-Hao, additional, Gilles, Marcous, additional, Glaab, Enrico, additional, Barnsley, Kelly, additional, Iyengar, Suhasini M., additional, Ondrechen, Mary Jo, additional, Haupt, V. Joachim, additional, Kaiser, Florian, additional, Schroeder, Michael, additional, Pugliese, Luisa, additional, Albani, Simone, additional, Athanasiou, Christina, additional, Beccari, Andrea, additional, Carloni, Paolo, additional, D'Arrigo, Giulia, additional, Gianquinto, Eleonora, additional, Goßen, Jonas, additional, Hanke, Anton, additional, Joseph, Benjamin P., additional, Kokh, Daria B., additional, Kovachka, Sandra, additional, Manelfi, Candida, additional, Mukherjee, Goutam, additional, Muñiz-Chicharro, Abraham, additional, Musiani, Francesco, additional, Nunes-Alves, Ariane, additional, Paiardi, Giulia, additional, Rossetti, Giulia, additional, Sadiq, S. Kashif, additional, Spyrakis, Francesca, additional, Talarico, Carmine, additional, Tsengenes, Alexandros, additional, Wade, Rebecca, additional, Copeland, Conner, additional, Gaiser, Jeremiah, additional, Olson, Daniel R., additional, Roy, Amitava, additional, Venkatraman, Vishwesh, additional, Wheeler, Travis J., additional, Arthanari, Haribabu, additional, Blaschitz, Klara, additional, Cespugli, Marco, additional, Durmaz, Vedat, additional, Fackeldey, Konstantin, additional, Fischer, Patrick D., additional, Gorgulla, Christoph, additional, Gruber, Christian, additional, Gruber, Karl, additional, Hetmann, Michael, additional, Kinney, Jamie E., additional, Das, Krishna M. Padmanabha, additional, Pandita, Shreya, additional, Singh, Amit, additional, Steinkellner, Georg, additional, Tesseyre, Guilhem, additional, Wagner, Gerhard, additional, Wang, Zi-Fu, additional, Yust, Ryan J., additional, Druzhilovskiy, Dmitry S., additional, Filimonov, Dmitry, additional, Pogodin, Pavel V., additional, Poroikov, Vladimir, additional, Rudik, Anastassia V., additional, Stolbov, Leonid A., additional, Veselovsky, Alexander V., additional, De Rosa, Maria, additional, Simone, Giada De, additional, Gulotta, Maria R., additional, Lombino, Jessica, additional, Mekni, Nedra, additional, Perricone, Ugo, additional, Casini, Arturo, additional, Embree, Amanda, additional, Gordon, D. Benjamin, additional, Lei, David, additional, Pratt, Katelin, additional, Voigt, Christopher A., additional, Chen, Kuang-Yu, additional, Jacob, Yves, additional, Krischuns, Tim, additional, Lafaye, Pierre, additional, Zettor, Agnès, additional, Rodríguez, M. Luis, additional, White, Kris M., additional, Fearon, Daren, additional, von Delft, Frank, additional, Walsh, Martin A., additional, Horvath, Dragos, additional, Brooks, Charles L., additional, Falsafi, Babak, additional, Ford, Bryan, additional, García-Sastre, Adolfo, additional, Lee, Sang Yup, additional, Naffakh, Nadia, additional, Varnek, Alexandre, additional, Klambauer, Guenter, additional, and Hermans, Thomas M., additional

Published
2023
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18. 12. Computer-based techniques for lead identification and optimization I: Basics

Author

Maruca, Annalisa, primary, Ambrosio, Francesca Alessandra, additional, Lupia, Antonio, additional, Romeo, Isabella, additional, Rocca, Roberta, additional, Moraca, Federica, additional, Talarico, Carmine, additional, Bagetta, Donatella, additional, Catalano, Raffaella, additional, Costa, Giosuè, additional, Artese, Anna, additional, and Alcaro, Stefano, additional

Published
2020
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19. 13. Computer-based techniques for lead identification and optimization II: Advanced search methods

Author

Lupia, Antonio, primary, Moraca, Federica, additional, Bagetta, Donatella, additional, Maruca, Annalisa, additional, Ambrosio, Francesca Alessandra, additional, Rocca, Roberta, additional, Catalano, Raffaella, additional, Romeo, Isabella, additional, Talarico, Carmine, additional, Ortuso, Francesco, additional, Artese, Anna, additional, and Alcaro, Stefano, additional

Published
2020
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21. Target Prediction by Multiple Virtual Screenings: Analyzing the SARS-CoV-2 Phenotypic Screening by the Docking Simulations Submitted to the MEDIATE Initiative.

Author

Gervasoni, Silvia, Manelfi, Candida, Adobati, Sara, Talarico, Carmine, Biswas, Akash Deep, Pedretti, Alessandro, Vistoli, Giulio, and Beccari, Andrea R.

Subjects
SARS-CoV-2, PHENOTYPES, FORECASTING, DECONVOLUTION (Mathematics)
Abstract

Phenotypic screenings are usually combined with deconvolution techniques to characterize the mechanism of action for the retrieved hits. These studies can be supported by various computational analyses, although docking simulations are rarely employed. The present study aims to assess if multiple docking calculations can prove successful in target prediction. In detail, the docking simulations submitted to the MEDIATE initiative are utilized to predict the viral targets involved in the hits retrieved by a recently published cytopathic screening. Multiple docking results are combined by the EFO approach to develop target-specific consensus models. The combination of multiple docking simulations enhances the performances of the developed consensus models (average increases in EF1% value of 40% and 25% when combining three and two docking runs, respectively). These models are able to propose reliable targets for about half of the retrieved hits (31 out of 59). Thus, the study emphasizes that docking simulations might be effective in target identification and provide a convincing validation for the collaborative strategies that inspire the MEDIATE initiative. Disappointingly, cross-target and cross-program correlations suggest that common scoring functions are not specific enough for the simulated target. [ABSTRACT FROM AUTHOR]

Published
2024
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22. DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action

Author

Iaconis, Daniela, primary, Caccuri, Francesca, additional, Manelfi, Candida, additional, Talarico, Carmine, additional, Bugatti, Antonella, additional, Filippini, Federica, additional, Zani, Alberto, additional, Novelli, Rubina, additional, Kuzikov, Maria, additional, Ellinger, Bernhard, additional, Gribbon, Philip, additional, Riecken, Kristoffer, additional, Esposito, Francesca, additional, Corona, Angela, additional, Tramontano, Enzo, additional, Beccari, Andrea Rosario, additional, Caruso, Arnaldo, additional, and Allegretti, Marcello, additional

Published
2023
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23. A community effort to discover small molecule SARS-CoV-2 inhibitors

Author

Schimunek, Johannes, primary, Seidl, Philipp, additional, Elez, Katarina, additional, Hempel, Tim, additional, Le, Tuan, additional, Noé, Frank, additional, Olsson, Simon, additional, Raich, Lluís, additional, Winter, Robin, additional, Gokcan, Hatice, additional, Gusev, Filipp, additional, Gutkin, Evgeny M., additional, Isayev, Olexandr, additional, Kurnikova, Maria G., additional, Narangoda, Chamali H., additional, Zubatyuk, Roman, additional, Bosko, Ivan P., additional, Furs, Konstantin V., additional, Karpenko, Anna D., additional, Kornoushenko, Yury V., additional, Shuldau, Mikita, additional, Yushkevich, Artsemi, additional, Benabderrahmane, Mohammed B., additional, Bousquet-Melou, Patrick, additional, Bureau, Ronan, additional, Charton, Beatrice, additional, Cirou, Bertrand C., additional, Gil, Gérard, additional, Allen, William J., additional, Sirimulla, Suman, additional, Watowich, Stanley, additional, Antonopoulos, Nick A., additional, Epitropakis, Nikolaos E., additional, Krasoulis, Agamemnon K., additional, Pitsikalis, Vassilis P., additional, Theodorakis, Stavros T., additional, Kozlovskii, Igor, additional, Maliutin, Anton, additional, Medvedev, Alexander, additional, Popov, Petr, additional, Zaretckii, Mark, additional, Eghbal-zadeh, Hamid, additional, Halmich, Christina, additional, Hochreiter, Sepp, additional, Mayr, Andreas, additional, Ruch, Peter, additional, Widrich, Michael, additional, Berenger, Francois, additional, Kumar, Ashutosh, additional, Yamanishi, Yoshihiro, additional, Zhang, Kam Y.J., additional, Bengio, Emmanuel, additional, Bengio, Yoshua, additional, Jain, Moksh J., additional, Korablyov, Maksym, additional, Liu, Cheng-Hao, additional, Marcou, Gilles, additional, Glaab, Enrico, additional, Barnsley, Kelly, additional, Iyengar, Suhasini M., additional, Ondrechen, Mary Jo, additional, Haupt, V. Joachim, additional, Kaiser, Florian, additional, Schroeder, Michael, additional, Pugliese, Luisa, additional, Albani, Simone, additional, Athanasiou, Christina, additional, Beccari, Andrea, additional, Carloni, Paolo, additional, D'Arrigo, Giulia, additional, Gianquinto, Eleonora, additional, Goßen, Jonas, additional, Hanke, Anton, additional, Joseph, Benjamin P., additional, Kokh, Daria B., additional, Kovachka, Sandra, additional, Manelfi, Candida, additional, Mukherjee, Goutam, additional, Muñiz-Chicharro, Abraham, additional, Musiani, Francesco, additional, Nunes-Alves, Ariane, additional, Paiardi, Giulia, additional, Rossetti, Giulia, additional, Sadiq, S. Kashif, additional, Spyrakis, Francesca, additional, Talarico, Carmine, additional, Tsengenes, Alexandros, additional, Wade, Rebecca C., additional, Copeland, Conner, additional, Gaiser, Jeremiah, additional, Olson, Daniel R., additional, Roy, Amitava, additional, Venkatraman, Vishwesh, additional, Wheeler, Travis J., additional, Arthanari, Haribabu, additional, Blaschitz, Klara, additional, Cespugli, Marco, additional, Durmaz, Vedat, additional, Fackeldey, Konstantin, additional, Fischer, Patrick D., additional, Gorgulla, Christoph, additional, Gruber, Christian, additional, Gruber, Karl, additional, Hetmann, Michael, additional, Kinney, Jamie E., additional, Padmanabha Das, Krishna M., additional, Pandita, Shreya, additional, Singh, Amit, additional, Steinkellner, Georg, additional, Tesseyre, Guilhem, additional, Wagner, Gerhard, additional, Wang, Zi-Fu, additional, Yust, Ryan J., additional, Druzhilovskiy, Dmitry S., additional, Filimonov, Dmitry A., additional, Pogodin, Pavel V., additional, Poroikov, Vladimir, additional, Rudik, Anastassia V., additional, Stolbov, Leonid A., additional, Veselovsky, Alexander V., additional, De Rosa, Maria, additional, De Simone, Giada, additional, Gulotta, Maria R., additional, Lombino, Jessica, additional, Mekni, Nedra, additional, Perricone, Ugo, additional, Casini, Arturo, additional, Embree, Amanda, additional, Gordon, D. Benjamin, additional, Lei, David, additional, Pratt, Katelin, additional, Voigt, Christopher A., additional, Chen, Kuang-Yu, additional, Jacob, Yves, additional, Krischuns, Tim, additional, Lafaye, Pierre, additional, Zettor, Agnès, additional, Rodríguez, M. Luis, additional, White, Kris M., additional, Fearon, Daren, additional, Von Delft, Frank, additional, Walsh, Martin A., additional, Horvath, Dragos, additional, Brooks III, Charles L., additional, Falsafi, Babak, additional, Ford, Bryan, additional, García-Sastre, Adolfo, additional, Lee, Sang Yup, additional, Naffakh, Nadia, additional, Varnek, Alexandre, additional, Klambauer, Günter, additional, and Hermans, Thomas M., additional

Published
2023
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24. MEDIATE - Molecular DockIng at homE: Turning collaborative simulations into therapeutic solutions

Author

Vistoli, Giulio, Manelfi, Candida, Talarico, Carmine, Fava, Anna, Warshel, Arieh, Tetko, Igor V., Apostolov, Rossen, Ye, Yang, Latini, Chiara, Ficarelli, Federico, Palermo, Gianluca, Gadioli, Davide, Vitali, Emanuele, Varriale, Gaetano, Pisapia, Vincenzo, Scaturro, Marco, Coletti, Silvano, Gregori, Daniele, Gruffat, Daniel, Leija, Edgardo, Hessenauer, Sam, Delbianco, Alberto, Allegretti, Marcello, Beccari, Andrea R., Vistoli, Giulio, Manelfi, Candida, Talarico, Carmine, Fava, Anna, Warshel, Arieh, Tetko, Igor V., Apostolov, Rossen, Ye, Yang, Latini, Chiara, Ficarelli, Federico, Palermo, Gianluca, Gadioli, Davide, Vitali, Emanuele, Varriale, Gaetano, Pisapia, Vincenzo, Scaturro, Marco, Coletti, Silvano, Gregori, Daniele, Gruffat, Daniel, Leija, Edgardo, Hessenauer, Sam, Delbianco, Alberto, Allegretti, Marcello, and Beccari, Andrea R.

Abstract

Introduction: Collaborative computing has attracted great interest in the possibility of joining the efforts of researchers worldwide. Its relevance has further increased during the pandemic crisis since it allows for the strengthening of scientific collaborations while avoiding physical interactions. Thus, the E4C consortium presents the MEDIATE initiative which invited researchers to contribute via their virtual screening simulations that will be combined with AI-based consensus approaches to provide robust and method-independent predictions. The best compounds will be tested, and the biological results will be shared with the scientific community. Areas covered: In this paper, the MEDIATE initiative is described. This shares compounds’ libraries and protein structures prepared to perform standardized virtual screenings. Preliminary analyses are also reported which provide encouraging results emphasizing the MEDIATE initiative’s capacity to identify active compounds. Expert opinion: Structure-based virtual screening is well-suited for collaborative projects provided that the participating researchers work on the same input file. Until now, such a strategy was rarely pursued and most initiatives in the field were organized as challenges. The MEDIATE platform is focused on SARS-CoV-2 targets but can be seen as a prototype which can be utilized to perform collaborative virtual screening campaigns in any therapeutic field by sharing the appropriate input files., QC 20230821

Published
2023
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25. Structure of human TRPM8 channel

Author

Palchevskyi, Sergii, primary, Czarnocki-Cieciura, Mariusz, additional, Vistoli, Giulio, additional, Gervasoni, Silvia, additional, Nowak, Elżbieta, additional, Beccari, Andrea, additional, Nowotny, Marcin, additional, and Talarico, Carmine, additional

Published
2023
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27. The SARS-CoV-2 spike protein binds and modulates estrogen receptors

Author

Solis, Oscar, primary, Beccari, Andrea R., additional, Iaconis, Daniela, additional, Talarico, Carmine, additional, Ruiz-Bedoya, Camilo A., additional, Nwachukwu, Jerome C., additional, Cimini, Annamaria, additional, Castelli, Vanessa, additional, Bertini, Riccardo, additional, Montopoli, Monica, additional, Cocetta, Veronica, additional, Borocci, Stefano, additional, Prandi, Ingrid G., additional, Flavahan, Kelly, additional, Bahr, Melissa, additional, Napiorkowski, Anna, additional, Chillemi, Giovanni, additional, Ooka, Masato, additional, Yang, Xiaoping, additional, Zhang, Shiliang, additional, Xia, Menghang, additional, Zheng, Wei, additional, Bonaventura, Jordi, additional, Pomper, Martin G., additional, Hooper, Jody E., additional, Morales, Marisela, additional, Rosenberg, Avi Z., additional, Nettles, Kendall W., additional, Jain, Sanjay K., additional, Allegretti, Marcello, additional, and Michaelides, Michael, additional

Published
2022
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28. The Spike Mutants Website: A Worldwide Used Resource against SARS-CoV-2

Author

Romeo, Isabella, primary, Prandi, Ingrid Guarnetti, additional, Giombini, Emanuela, additional, Gruber, Cesare Ernesto Maria, additional, Pietrucci, Daniele, additional, Borocci, Stefano, additional, Abid, Nabil, additional, Fava, Anna, additional, Beccari, Andrea R., additional, Chillemi, Giovanni, additional, and Talarico, Carmine, additional

Published
2022
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29. Structure of human TRPM8 channel

Author

Palchevskyi, Sergii, primary, Czarnocki-Cieciura, Mariusz, additional, Vistoli, Giulio, additional, Gervasoni, Silvia, additional, Nowak, Elżbieta, additional, Beccari, Andrea R., additional, Nowotny, Marcin, additional, and Talarico, Carmine, additional

Published
2022
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30. Relevance of the viral Spike protein/cellular Estrogen Receptor-α interaction for endothelial-based coagulopathy induced by SARS-CoV-2

Author

Barbieri, Silvia, primary, Cattani, Franca, additional, Sandrini, Leonardo, additional, Grillo, Magda Maria, additional, Talarico, Carmine, additional, Iaconis, Daniela, additional, Lione, Lucia, additional, Salvatori, Erika, additional, Amadio, Patrizia, additional, Garoffolo, Gloria, additional, Maffei, Mariano, additional, Galli, Francesca, additional, Beccari, Andrea Rosario, additional, Marra, Emanuele, additional, Zoppi, Marica, additional, Michaelides, Michael, additional, Roscilli, Giuseppe, additional, Aurisicchio, Luigi, additional, Bertini, Riccardo, additional, Allegretti, Marcello, additional, and Pesce, Maurizio, additional

Published
2022
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36. Natural Compounds Inhibit SARS-CoV-2 nsp13 Unwinding and ATPase Enzyme Activities

Author

Corona, Angela, primary, Wycisk, Krzysztof, additional, Talarico, Carmine, additional, Manelfi, Candida, additional, Milia, Jessica, additional, Cannalire, Rolando, additional, Esposito, Francesca, additional, Gribbon, Philip, additional, Zaliani, Andrea, additional, Iaconis, Daniela, additional, Beccari, Andrea R., additional, Summa, Vincenzo, additional, Nowotny, Marcin, additional, and Tramontano, Enzo, additional

Published
2022
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38. Characterization of raloxifene as potential pharmacological agent against SARS-CoV-2 and its variants

Author

Iaconis, Daniela, primary, Talarico, Carmine, additional, Manelfi, Candida, additional, Cesta, Maria Candida, additional, Zippoli, Mara, additional, Caccuri, Francesca, additional, Matusali, Giulia, additional, Bordi, Licia, additional, Scorzolini, Laura, additional, Bucci, Enrico, additional, Caruso, Arnaldo, additional, Nicastri, Emanuele, additional, Allegretti, Marcello, additional, and Beccari, Andrea Rosario, additional

Published
2021
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40. Combining Different Docking Engines and Consensus Strategies to Design and Validate Optimized Virtual Screening Protocols for the SARS-CoV-2 3CL Protease

Author

Manelfi, Candida, Gossen, Jonas, Pedretti, Alessandro, Gervasoni, Silvia, Talarico, Carmine, Albani, Simone, Philipp, Benjamin Joseph, Musiani, Francesco, Vistoli, Giulio, Rossetti, Giulia, Beccari, Andrea Rosario, Manelfi C., Gossen J., Gervasoni S., Talarico C., Albani S., Philipp B.J., Musiani F., Vistoli G., Rossetti G., Beccari A.R., and Pedretti A.

Subjects
Models, Molecular, Coronavirus 3C Protease, Protein Conformation, Protease Inhibitor, Drug Evaluation, Preclinical, Antiviral Agents, Article, lcsh:QD241-441, antivirals, docking simulation, binding space, lcsh:Organic chemistry, Humans, consensus models, Protease Inhibitors, Coronavirus 3C Proteases, Antiviral Agent, docking simulations, Binding Sites, drug repurposing, SARS-CoV-2, Binding Site, Drug Repositioning, COVID-19, virtual screening, antiviral, consensus model, COVID-19 Drug Treatment, Molecular Docking Simulation, Peptide Hydrolase, Drug Design, ddc:540, isomeric space, 3CL-Pro, Peptide Hydrolases, Human
Abstract

Molecules : a journal of synthetic chemistry and natural product chemistry 26(4), 797 (2021). doi:10.3390/molecules26040797 special issue: "Computational Approaches: Drug Discovery and Design in Medicinal Chemistry and Bioinformatics / Special Issue Editors: Dr. Marco Tutone, Guest Editor; Prof. Dr. Anna Maria Almerico, Guest Editor", Published by Springer, Berlin ; Heidelberg

Published
2021

41. Additional file 1 of 'Molecular Anatomy': a new multi-dimensional hierarchical scaffold analysis tool

Author

Manelfi, Candida, Gemei, Marica, Talarico, Carmine, Cerchia, Carmen, Fava, Anna, Lunghini, Filippo, and Beccari, Andrea Rosario

Abstract

Additional file 1: Figure S1. Cytoscape network visualization of the 816 COX-2 inhibitors subset where nodes includes fragments related to the basic wireframe representation, contributing to create a fully connected unique network. Figure S2. The fragments extracted from the basic wireframe representation, with the highest number of connections (indegree) in the Cytoscape network visualization reported in Figure S1. Figure S3. Selection of the most interesting basic wireframe, corresponding to the most abstracted representation in common within each cluster of the network, filtered by the highest values of EF and number of connected active molecules of the corresponding cluster.

Published
2021
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42. A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics

Author

Gossen, Jonas, Albani, Simone, Hanke, Anton, Joseph, Benjamin P., Bergh, Cathrine, Kuzikov, Maria, Costanzi, Elisa, Manelfi, Candida, Storici, Paola, Gribbon, Philip, Beccari, Andrea R., Talarico, Carmine, Spyrakis, Francesca, Lindahl, Erik, Zaliani, Andrea, Carloni, Paolo, Wade, Rebecca C., Musiani, Francesco, Kokh, Daria B., Rossetti, Giulia, Gossen, Jonas, Albani, Simone, Hanke, Anton, Joseph, Benjamin P., Bergh, Cathrine, Kuzikov, Maria, Costanzi, Elisa, Manelfi, Candida, Storici, Paola, Gribbon, Philip, Beccari, Andrea R., Talarico, Carmine, Spyrakis, Francesca, Lindahl, Erik, Zaliani, Andrea, Carloni, Paolo, Wade, Rebecca C., Musiani, Francesco, Kokh, Daria B., and Rossetti, Giulia

Abstract

The SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of similar to 30 000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing similar to 200 virtual screenings of compound libraries on selected protein structures, we redefine the protein's druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro inhibitors to SARS-CoV-2 Mpro, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro, that were validated by in vitro assays performed here and by a newly solved X-ray crystal structure. These results provide a strong basis for effective rational drug design campaigns against SARS-CoV-2 Mpro and a new computational approach to screen protein targets with malleable binding sites., QC 20210719

Published
2021
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45. A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics

Author

Gossen, Jonas, primary, Albani, Simone, additional, Hanke, Anton, additional, Joseph, Benjamin P., additional, Bergh, Cathrine, additional, Kuzikov, Maria, additional, Costanzi, Elisa, additional, Manelfi, Candida, additional, Storici, Paola, additional, Gribbon, Philip, additional, Beccari, Andrea R., additional, Talarico, Carmine, additional, Spyrakis, Francesca, additional, Lindahl, Erik, additional, Zaliani, Andrea, additional, Carloni, Paolo, additional, Wade, Rebecca C., additional, Musiani, Francesco, additional, Kokh, Daria B., additional, and Rossetti, Giulia, additional

Published
2021
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46. Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen

Author

Kuzikov, Maria, primary, Costanzi, Elisa, additional, Reinshagen, Jeanette, additional, Esposito, Francesca, additional, Vangeel, Laura, additional, Wolf, Markus, additional, Ellinger, Bernhard, additional, Claussen, Carsten, additional, Geisslinger, Gerd, additional, Corona, Angela, additional, Iaconis, Daniela, additional, Talarico, Carmine, additional, Manelfi, Candida, additional, Cannalire, Rolando, additional, Rossetti, Giulia, additional, Gossen, Jonas, additional, Albani, Simone, additional, Musiani, Francesco, additional, Herzog, Katja, additional, Ye, Yang, additional, Giabbai, Barbara, additional, Demitri, Nicola, additional, Jochmans, Dirk, additional, Jonghe, Steven De, additional, Rymenants, Jasper, additional, Summa, Vincenzo, additional, Tramontano, Enzo, additional, Beccari, Andrea R., additional, Leyssen, Pieter, additional, Storici, Paola, additional, Neyts, Johan, additional, Gribbon, Philip, additional, and Zaliani, Andrea, additional

Published
2021
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47. A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0

Author

Gervasoni, Silvia, Vistoli, Giulio, Talarico, Carmine, Manelfi, Candida, Beccari, Andrea R., Studer, Gabriel, Tauriello, Gerardo, Waterhouse, Andrew Mark, Schwede, Torsten, and Pedretti, Alessandro

Subjects
docking simulations, pocket druggability, Binding Sites, Protein Conformation, SARS-CoV-2, Pneumonia, Viral, Drug Repositioning, COVID-19, pocket search, virtual screening, Antiviral Agents, Article, blind docking, Molecular Docking Simulation, lcsh:Chemistry, Betacoronavirus, Viral Proteins, lcsh:Biology (General), lcsh:QD1-999, Humans, Coronavirus Infections, Pandemics, lcsh:QH301-705.5, Protein Binding
Abstract

(1) Background: Virtual screening studies on the therapeutically relevant proteins of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) require a detailed characterization of their druggable binding sites, and, more generally, a convenient pocket mapping represents a key step for structure-based in silico studies, (2) Methods: Along with a careful literature search on SARS-CoV-2 protein targets, the study presents a novel strategy for pocket mapping based on the combination of pocket (as performed by the well-known FPocket tool) and docking searches (as performed by PLANTS or AutoDock/Vina engines), such an approach is implemented by the Pockets 2.0 plug-in for the VEGA ZZ suite of programs, (3) Results: The literature analysis allowed the identification of 16 promising binding cavities within the SARS-CoV-2 proteins and the here proposed approach was able to recognize them showing performances clearly better than those reached by the sole pocket detection, and (4) Conclusions: Even though the presented strategy should require more extended validations, this proved successful in precisely characterizing a set of SARS-CoV-2 druggable binding pockets including both orthosteric and allosteric sites, which are clearly amenable for virtual screening campaigns and drug repurposing studies. All results generated by the study and the Pockets 2.0 plug-in are available for download.

Published
2020

48. Computational Studies of SARS-CoV-2 3CLpro : Insights from MD Simulations

Author

Grottesi, Alessandro, Bešker, Neva, Emerson, Andrew, Manelfi, Candida, Beccari, Andrea R., Frigerio, Francesco, Lindahl, Erik, Cerchia, Carmen, Talarico, Carmine, Grottesi, Alessandro, Bešker, Neva, Emerson, Andrew, Manelfi, Candida, Beccari, Andrea R., Frigerio, Francesco, Lindahl, Erik, Cerchia, Carmen, and Talarico, Carmine

Abstract

Given the enormous social and health impact of the pandemic triggered by severe acute respiratory syndrome 2 (SARS-CoV-2), the scientific community made a huge effort to provide an immediate response to the challenges posed by Coronavirus disease 2019 (COVID-19). One of the most important proteins of the virus is an enzyme, called 3CLpro or main protease, already identified as an important pharmacological target also in SARS and Middle East respiratory syndrome virus (MERS) viruses. This protein triggers the production of a whole series of enzymes necessary for the virus to carry out its replicating and infectious activities. Therefore, it is crucial to gain a deeper understanding of 3CLpro structure and function in order to effectively target this enzyme. All-atoms molecular dynamics (MD) simulations were performed to examine the different conformational behaviors of the monomeric and dimeric form of SARS-CoV-2 3CLpro apo structure, as revealed by microsecond time scale MD simulations. Our results also shed light on the conformational dynamics of the loop regions at the entry of the catalytic site. Studying, at atomic level, the characteristics of the active site and obtaining information on how the protein can interact with its substrates will allow the design of molecules able to block the enzymatic function crucial for the virus.

Published
2020
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50. Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in-vitro repurposing screen

Author

Kuzikov, Maria, primary, Costanzi, Elisa, additional, Reinshagen, Jeanette, additional, Esposito, Francesca, additional, Vangeel, Laura, additional, Wolf, Markus, additional, Ellinger, Bernhard, additional, Claussen, Carsten, additional, Geisslinger, Gerd, additional, Corona, Angela, additional, Iaconis, Daniela, additional, Talarico, Carmine, additional, Manelfi, Candida, additional, Cannalire, Rolando, additional, Rossetti, Giulia, additional, Gossen, Jonas, additional, Albani, Simone, additional, Musiani, Francesco, additional, Herzog, Katja, additional, Ye, Yang, additional, Giabbai, Barbara, additional, Demitri, Nicola, additional, Jochmans, Dirk, additional, De Jonghe, Steven, additional, Rymenants, Jasper, additional, Summa, Vincenzo, additional, Tramontano, Enzo, additional, Beccari, Andrea R., additional, Leyssen, Pieter, additional, Storici, Paola, additional, Neyts, Johan, additional, Gribbon, Philip, additional, and Zaliani, Andrea, additional

Published
2020
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