Identification of Potential inhibitors of the SARS-CoV-2 NSP13 Helicase via Structure-Based Ligand Design, Molecular Docking and Nonequilibrium Alchemical Simulations

: We have assembled a computational pipeline   based on virtual screening, docking techniques, and nonequilibrium   molecular dynamics simulations,  with the goal of identifying possible   inhibitors of the SARS-CoV-2 NSP13 helicase, catalyzing by ATP   hydrolysis the unwinding of double or single-stranded RNA in the   viral replication process inside the host cell. The druggable sites   for broad-spectrum inhibitors are represented by the RNA binding sites at   the 5' entrance and 3' exit of the central channel, a structural motif   that is highly conserved across coronaviruses. Potential binders   were first generated using structure-based ligand techniques. Their   potency was assessed by using four popular docking scoring   functions. Common docking hits for NSP13 were finally tested   using advanced nonequilibrium alchemical techniques for binding free energy calculations on a high-performing parallel cluster. Four potential NSP13 inhibitors with potency from submicrimolar to nanomolar were finally identified.