Supercomputing, Docking and Quantum Mechanics in Quest for Inhibitors of Papain-like Protease of SARS-CoV-2

Sulimov, A. V.; Ilin, I. S.; Kutov, D. C.; Stolpovskaya, N. V.; Shikhaliev, Kh. S.; Sulimov, V. B.

Lomonosov-2 supercomputer is used to search for new organic compounds that can suppress the replication of the SARS-CoV-2 coronavirus. The latter is responsible for the COVID-19 pandemic. Docking and a quantum-chemical semiempirical atomistic modeling method are used to find inhibitors of the SARS-CoV-2 papain-like protease, which is one of the key coronavirus enzymes responsible for its replication. The atomistic model of the papain-like protease of this coronavirus is based on the high-resolution structure deposited in the Protein Data Bank. The SOL docking program has been used for virtual screening of more than [Formula: see text] low molecular weight molecules (ligands). Ligands with the highest protein-ligand binding energy, selected using the docking results, were subjected to quantum-chemical calculations. The latters are performed by the PM7 semiempirical method with the COSMO implicit solvent model using the MOPAC program. The enthalpy of protein-ligand binding is calculated for the best position of the ligand in the protein. [Formula: see text] ligands were selected for experimental in vitro testing as candidates for papain-like protease inhibitors base on docking and quantum-chemical results. In case of experimental confirmation, these compounds may become the basis for direct-acting antiviral drugs for the SARS-CoV-2 coronavirus.