LAUSR

Protease inhibitors (PIs) are crucial drugs in highly active antiretroviral therapy for human immunodeficiency virus‐1 (HIV‐1) infections. However, resistance owing to mutations challenge the long‐term efficacy in the medication of HIV‐1‐infected individuals. Lopinavir (LPV) and darunavir (DRV), two second‐generation drugs are the most potent among PIs, hustling the drug resistance when mutations occur in the active and nonactive site of the protease (PR). Herein, we strive for compounds that can stifle the function of wild‐type (WT) HIV‐1 PR along with four major single mutants (I54M, V82T, I84V, and L90M) instigating resistance to the PIs using in silico approach. Six common compounds are retrieved from six databases using combined pharmacophore‐based and structure‐based virtual screening methodology. LPV and DRV are docked and the binding free energy is calculated to set the cut‐off value for selecting compounds. Further, to gain insight into the stability of the complexes the molecular dynamics simulation (MDS) is carried out, which uncovers two lead molecules namely NCI‐524545 and ZINC12866729. Both the lead molecules connect with WT and mutant HIV‐1 PRs through strong and stable hydrogen bond interactions when compared with LPV and DRV throughout the trajectory analysis. Interestingly, NCI‐524545 and ZINC12866729 exhibit direct interactions with I50/50′ by replacing the conserved water molecule as evidenced by MDS, which indicates the credible potency of these compounds. Hence, we concluded that NCI‐524545 and ZINC12866729 have great puissant to restrain the role of drug resistance HIV‐1 PR variants, which can also show better activity through in vivo and in vitro conditions.