Design of new chemical entities targeting both native and H275Y mutant influenza a virus by deep reinforcement learning.

Influenza virus remains a major public health challenge due to its high morbidity and mortality and seasonal surge. Although antiviral drugs against the influenza virus are widely used as a first-line defense, the virus undergoes rapid genetic changes, resulting in the emergence of drug-resistant strains. Thus, new antiviral drugs that can outwit resistant strains are of significant importance. Herein, we used deep reinforcement learning (RL) algorithm to design new chemical entities (NCEs) that are able to bind to the native and H275Y mutant (oseltamivir-resistant) neuraminidases (NAs) of influenza A virus with better binding energy than oseltamivir. We generated more than 66211 NCEs, which were prioritized based on the filtering rules, structural alerts, and synthetic accessibility. Then, 18 NCEs with better MM/PBSA scores than oseltamivir were further analyzed in molecular dynamics (MD) simulations conducted for 100 ns. The MD experiments showed that 8 NCEs formed very stable complexes with the binding pocket of both native and H275Y mutant NAs of H1N1. Furthermore, most NCEs demonstrated much better binding affinity to group 2 (N2, N3, and N9) and influenza B virus NAs than oseltamivir. Although all 8 NCEs have non-sialic acid-like structures, they showed a similar binding mode as oseltamivir, indicating that it is possible to find new scaffolds with better binding and antiviral properties than sialic acid-like inhibitors. In conclusion, we have designed potential compounds as antiviral candidates for further synthesis and testing against wild and mutant influenza virus.Communicated by Ramaswamy H. Sarma.