Programme

O.9 -- Oral, VCTP-46

Date: Monday, 4 October 2021

Time: 17:10 - 17:30

Investigating structural differences of the SARS-CoV-2 Mpro binding site before and after covalent bond formation with ligands: enabling efficient and accurate virtual screening campaigns.

Hien T. T. Lai (1), Giulia Rossetti (2, 3, 4), Toan T. Nguyen (1), Paolo Carloni (2, 5, 6) and Agata Kranjc (2, 7, 8)

(1) VNU Key Laboratory for Multiscale Simulation of Complex Systems, VNU University of Science, Vietnam National University, Hanoi, 11416, Vietnam; (2) Institute of Neuroscience and Medicine (INM-9)/Institute for Advanced Simulation (IAS-5), Forschungszentrum Jülich, D-52425 Jülich, Germany; (3) Jülich Supercomputing Center (JSC), Forschungszentrum Jülich, 52428 Jülich, Germany; (4) University Hospital Aachen, RWTH Aachen University, 52078 Aachen, Germany; (5) RWTH Aachen University, Department of Physics, 52078 Aachen, Germany; (6) JARA-BRAIN Institute "Molecular Neuroscience and Neuroimaging" INM-11, Forschungszentrum Jülich, 52428, Jülich, Germany; (7) CNRS, Université de Paris, UPR 9080, Laboratoire de Biochimie Théorique, 13 rue Pierre et Marie Curie, F-75005, Paris, France; (8) Institut de Biologie Physico-Chimique-Fondation Edmond de Rotschild, PSL Research University, Paris, France;

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the COVID-19 disease became a global public-health emergency. The SARS-CoV-2 main protease (SARS-CoV-2 Mpro) plays an important role in the viral transcription and replication, therefore it is among the best-characterized proteins of SARS-CoV-2 virus and represents a very attractive target for drug development. It is extremely important to find drugs for the SARS-CoV-2 Mpro binding site. Most of known ligands bind covalently to this target, however it is computationally unfeasible a virtual screening of millions of compounds accurately including covalent bond formation. In this project we will study and characterize in-silico the detailed structure of the binding pocket of the protein (possibly quite different from the crystallographic apo structure) in presence of effective inhibitors (molecules 11a and 11b, where X-ray structures have been obtained) before and after the formation of the covalent bond. This will open the possibility to perform effective non-covalent virtual screening of millions of compounds while retaining high chances of finding good covalent ligands. The outcome of this study will therefore provide an essential tool to accelerate the search of drugs in the scientific community performing computer aided drug design.

Presenter: Lai Thi Thu Hien