5/2/2023 0 Comments Singlebox appNew irreversible covalent inhibitors for SARS-CoV-2 3CL pro were recently proposed in ref (5). 3CL pro-based drug discovery for SARS (10) was mainly directed toward the so-called covalent Michael inhibitors (11,12) via electrophilic attack on the cysteinate of the 3CL pro catalytic CYS145–HIS41 dyad. (9) It is hence expected that inhibitors for SARS-CoV 3CL pro bind effectively the strictly related SARS-CoV-2 main protease. (6) The main protease of SARS-CoV (7)and SARS-CoV-2 (2,5,8) differs by only 12 residues, with none of these differing residues being directly involved in the catalytic site. Indeed, the RNA of SARS-CoV-2 and of SARS-CoV share nearly 80% genomic sequence identity. One of the main approaches for anti-Covid-19 drug development is based on past experience on the SARS 2003 outbreak. (4,5) It is hence expected that a potent and specific inhibitor of 3CL pro can effectively block the viral replication once the virions have entered the cell. For example, the virus replication machinery itself, the RNA-dependent RNA polymerase (RdRp), is generated upon 3CL pro cleavage of pp1a, pp1ab. The cleavage on multiple points of these polyproteins releases in the infected cell mature nonstructural proteins that are important for virus replication. (3) This protein is responsible for the cleavage of pp1a and pp1ab large polyproteins expressed by the virus RNA upon cell entry. Indeed, inhibition of 3CL pro using small molecules is currently the main goal of the crowdsourcing drug discovery initiative for pandemics. Among the viral functional proteins, the main protease 3CL pro (1,2) constitutes a very attractive biomolecular target for drug design. We have identified several noncongeneric compounds with predicted low micromolar activity for 3CL pro inhibition, which may constitute possible lead compounds for the development of antiviral agents in Covid-19 treatment.Īs the whole world is currently plagued by the Covid-19 pandemic, the race to identify an effective antiviral agent for SARS-CoV-2 is frantically ongoing. The nature of binding in the 3CL pro active site and the involved residues besides the CYS–HYS catalytic dyad have been thoroughly characterized by enhanced sampling simulations of the bound state. The calculated binding free energies for four additional ligands with known activity (either for SARS-CoV or SARS-CoV-2 main protease) are also reported. The core structures of 3CL pro ligands were previously identified using a multimodal structure-based ligand design in combination with docking techniques. The method has been applied for the determination of absolute binding free energies of 16 newly designed noncovalent ligands of the main protease (3CL pro) of SARS-CoV-2. In the context of drug–receptor binding affinity calculations using molecular dynamics techniques, we implemented a combination of Hamiltonian replica exchange (HREM) and a novel nonequilibrium alchemical methodology, called virtual double-system single-box, with increased accuracy, precision, and efficiency with respect to the standard nonequilibrium approaches.
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