Computer-Aided Perspective for the Design of Flexible HIV Non- Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): de-novo Drug Design, Virtual Screening and Molecular Dynamics Simulations

Flexible hydroquinone-based compounds were previously proposed as potential mutant-resistant NNRTIs inhibitors, however, experimental or computational evidences did not support this proposal. Herewith, using an integrated in-silico computational approach involving de-novo drug design, structure-based virtual screening (SBVS), molecular dynamics simulations and post-dynamic per-residue binding energy decomposition analysis, the binding affinity as well as the interaction landscape of novel flexible hydroquinone-based compounds were investigated to explore their activity as potential NNRTIs. The proposed leads were found to exhibit improved binding affinity when compared to FDA-approved NNRTIs, rilpvirine, nevirapine and efavirenz, however, the bioavailability profile of these compounds could hamper their uses as effective drugs. Results obtained from this extensive study could assist medicinal and biochemistry researchers with further experimental investigations.