HPC-DRIVEN HIT-TO-LEAD PROCESS FOR SARS-COV-2 MAIN PROTEASE INHIBITION

In this contribution, we present a molecular dynamics-based technique for the calculation of the absolute binding free energies (ABFE) in drug-receptor systems. The technique, called virtual double system single box (vDSSB), is a versatile nonequilibrium variant of the so-called alchemical approach for ABFE calculation, specifically tailored for homogenous and heterogenous high-performing computing platforms. The technique has been applied to the calculation of potential non-covalent inhibitors of the main protease of the SARS-CoV-2 virus. We report here the results obtained in the summer 2020 on the CRESCO6 facilities using the program ORAC [M. Macchiagodena et al., J. Chem. Theory Comput. 16, 7160 (2020), P. Procacci et al., Chem. Comm., 56, 8854 (2020)] on a series of ligands selected as docking hits from a previous virtual screening study. The algorithm has been further adapted to the GROMACS code and tested successfully on the Marconi100 heterogeneous architecture at CINECA.