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A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics.
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 J; Institute for Neuroscience and Medicine (INM-9), Forschungszentrum Jülich, Jülich, 52425, Germany.
  • Albani S; Institute for Advanced Simulations (IAS-5) "Computational biomedicine", Forschungszentrum Jülich, Jülich, 52425, Germany.
  • Hanke A; Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen, Aachen, 52062, Germany.
  • Joseph BP; Institute for Neuroscience and Medicine (INM-9), Forschungszentrum Jülich, Jülich, 52425, Germany.
  • Bergh C; Institute for Advanced Simulations (IAS-5) "Computational biomedicine", Forschungszentrum Jülich, Jülich, 52425, Germany.
  • Kuzikov M; Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen, Aachen, 52062, Germany.
  • Costanzi E; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Schloss-Wolfsbrunnenweg 35, Heidelberg, 69118, Germany.
  • Manelfi C; Institute of Pharmacy and Molecular Biotechnology (IPMB), Heidelberg University, Im Neuenheimer Feld 364, Heidelberg, 69120, Germany.
  • Storici P; Institute for Neuroscience and Medicine (INM-9), Forschungszentrum Jülich, Jülich, 52425, Germany.
  • Gribbon P; Institute for Advanced Simulations (IAS-5) "Computational biomedicine", Forschungszentrum Jülich, Jülich, 52425, Germany.
  • Beccari AR; Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen, Aachen, 52062, Germany.
  • Talarico C; Science for Life Laboratory & Swedish e-Science Research Center, Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, 11428, Sweden.
  • Spyrakis F; Department of Screening Port, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, Hamburg, 22525, Germany.
  • Lindahl E; Elettra-Sincrotrone Trieste S.C.p.A., SS 14-km 163,5 in AREA Science Park, Basovizza, Trieste, 34149, Italy.
  • Zaliani A; Dompé Farmaceutici SpA, Via Campo di Pile, L'Aquila, 67100, Italy.
  • Carloni P; Elettra-Sincrotrone Trieste S.C.p.A., SS 14-km 163,5 in AREA Science Park, Basovizza, Trieste, 34149, Italy.
  • Wade RC; Department of Screening Port, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, Hamburg, 22525, Germany.
  • Musiani F; Dompé Farmaceutici SpA, Via Campo di Pile, L'Aquila, 67100, Italy.
  • Kokh DB; Dompé Farmaceutici SpA, Via Campo di Pile, L'Aquila, 67100, Italy.
  • Rossetti G; Department of Drug Science and Technology, University of Turin, via Giuria 9, Turin, 10125, Italy.
ACS Pharmacol Transl Sci ; 4(3): 1079-1095, 2021 Jun 11.
Article in English | MEDLINE | ID: covidwho-1185367
Preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
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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 ∼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 ∼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.

Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Journal: ACS Pharmacol Transl Sci Year: 2021 Document Type: Article Affiliation country: Acsptsci.0c00215

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Journal: ACS Pharmacol Transl Sci Year: 2021 Document Type: Article Affiliation country: Acsptsci.0c00215