HIV-1 protease (HIV-1 PR) is a critical therapeutic target for HIV treatment, yet the development of novel inhibitors with improved efficacy remains a significant challenge. This study investigates the molecular mechanisms underlying the binding of three diastereoisomers of the novel phosphinate pseudopeptide inhibitor PAC-Phe-Val (SSSS, SRSS, SRRS) to HIV-1 PR in comparison with Darunavir, a clinically approved inhibitor. Using molecular dynamics simulations and MM/PBSA calculations, we characterized protein stability, flap dynamics, and allosteric communication networks within the protease-inhibitor complexes. Our results revealed that the SRSS isomer conferred superior structural stabilization comparable to Darunavir by suppressing global protein flexibility and maintaining a closed, catalytically inactive flap conformation. Importantly, SRSS disrupted key allosteric communication pathways within the protease. MM/PBSA analysis indicated that SRSS exhibited the highest binding affinity (-11.76 kcal/mol) among the designed inhibitors, driven primarily by a strong salt bridge interaction with the Arg8 residue. However, a substantial solvation penalty limited its overall binding affinity relative to Darunavir (-15.75 kcal/mol). These findings identify SRSS as a promising lead compound for HIV-1 PR inhibitor development. Our work provides atomic-level mechanistic insights into inhibitor binding and suggests that future optimization strategies should focus on reducing ligand polarity to minimize desolvation penalties and enhance binding affinity.
Xie et al. (Fri,) studied this question.