Structure-Guided Design and Development of a Phosphinic Lopinavir Analog as a Potent and Selective HIV-1 Protease Inhibitor

Human immunodeficiency virus (HIV) remains a significant health issue with no vaccine available. Targeting the HIV-1 protease (HIV-1 PR) is essential in treatment, with inhibitors like lopinavir being historically an important component. However, lopinavir alone has low bioavailability and causes side effects when combined with ritonavir, leading to efforts to develop improved analogs. In this study, we designed and synthesized a phosphinic analog of lopinavir, PL1, by replacing its hydroxyethylene moiety with a phosphinic group. The inhibitory evaluation demonstrated a promising inhibition potency of PL1 against HIV-1 PR, supported by molecular dynamics simulations predicting its favorable interactions. Integrating AI-based docking tools confirmed PL1’s strong potential, with an IC 50 /EC 50 of 1.32 × 10 −8 mol/L and a binding affinity of 6.142, surpassing lopinavir’s 5.928. PL1’s binding efficacy index of 0.0119, comparable to lopinavir’s 0.0132, indicates efficient inhibition. Importantly, PL1 is less toxic than lopinavir, making it a promising lead molecule for HIV-1 PR targeting.