P1 and P1′ para-fluoro phenyl groups show enhanced binding and favorable predicted pharmacological properties: Structure-based virtual screening of extended lopinavir analogs against multi-drug resistant HIV-1 protease

•Three libraries of extended lopinavir analogs were designed for docking analysis.•Lead compound (14) with favorable binding and pharmacological properties was identified using virtual screening.•Compound 14 has para-fluoro phenyl groups as P1 and P1′ moieties.•Compound 14 showed favorable binding affinity against wild type and an ensemble of MDR HIV-1 protease variants.•Compound 14 restored lost contacts in the expanded active site cavity of MDR HIV-1 protease.•Compound 14 showed favorable pharmacological properties as other FDA approved protease inhibitors. Crystal structure of multidrug-resistant (MDR) clinical isolate 769, human immunodeficiency virus type-1 (HIV-1) protease in complex with lopinavir (LPV) (PDB ID: 1RV7) showed altered binding orientation of LPV in the expanded active site cavity, causing loss of contacts and decrease in potency. In the current study, with a goal to restore the lost contacts, three libraries of LPV analogs containing extended P1 and/or P1′ phenyl groups were designed and docked into the expanded active site cavity of the MDR769 HIV-1 protease. The compounds were then ranked based on three criteria: binding affinity, overall binding profile and predicted pharmacological properties. Among the twelve proposed extensions in different combinations, compound 14 (consists of para-fluoro phenyl group as both P1 and P1′ moieties) was identified as a lead with improved binding profile, binding affinity against the MDR protease and favorable predicted pharmacological properties comparable to those of LPV. The binding affinity of 14 against wild type (NL4-3) HIV-1 protease was comparable to that of LPV and was better than LPV against an ensemble of MDR HIV-1 protease variants. Thus, 14 shows enhanced binding affinity by restoring lost contacts in the expanded active site cavity of MDR769 HIV-1 protease variants suggesting that it may have higher potency compared to that of LPV and hence should be further synthesized and evaluated against NL4-3 as well as MDR variants of HIV-1.