Molecular dynamics simulations and MM-GBSA reveal a novel small molecule against Flu A RNA-dependent RNA polymerase

The interaction between the C-terminal domain (CTD) of the polymerase acidic (PA) component of three Flu A RNA polymerases of different origins and three heptad repeats from human polymerase II CTD was computationally recreated. Then a unique pharmacological library was tested in order to target conserved active site residues in the three RNA-dependent RNA polymerase (RdRps) using a combination of molecular dynamics simulation and molecular docking. Results show that one compound (ZINC66032798) can effectively bind to the desired active site residues in each of the three RdRps. Hence, it may possess an inhibitory action by competing with human polymerase II CTD binding to the same active site of the viruses. The current in silico analysis suggests a promising novel lead to block Flu A RdRp, yet to be confirmed in the wet lab. It decreases the binding affinity of influenza A viruses to human polymerase II by 47.9%, 67.2%, and 28.0%, respectively.Communicated by Ramaswamy H. Sarma.