Predicting binding strength and dissociation kinetics of HIV-1 protease inhibitors Ritonavir, XK-263, and AHA-001 by molecular simulations

Protein-ligand interactions are essential in developing new drugs for targeted drug delivery. Ritonavir, XK263, and AHA001 are inhibitors that can bind to Human Immunodeficiency Virus-1 (HIV-1) protease to disrupt its enzymatic activity. However, various dynamic intracellular environments can develop a harmonic force, ultimately dissociating these ligands from the HIV-1 binding pocket, which are essential to study. Molecular dynamics (MD) simulations enable a platform to efficiently visualize and quantify the bound-unbound states of these ligand molecules in the presence of applied harmonic forces. We investigate the unbinding of Ritonavir, XK263, and AHA001 molecules from the HIV-1 protease dimer using an all-atom Steered Molecular Dynamics (SMD) simulation that induces an external stimulus as a constant harmonic force. The potential of mean force (PMF) calculations from the trajectories generated by SMD simulations show insights into the free energy landscape associated with the ligand's dissociation from HIV-1 protease, including the energetic barriers and favorable interactions involved in the process. Our results show that Ritonavir, a Food and Drug Administration (FDA), USA approved antiretroviral drug for HIV-1, has enhanced binding strength, followed by AHA001, which also shows a strong binding affinity comparable to many other FDA-approved drugs, as evidenced by the binding free energy calculations derived from Umbrella Sampling (US) simulations. The transient variations of corresponding protein-ligand interaction energies and calculations for hydrogen bond formation agree with the earlier findings. The predictions contribute to understanding how these three ligands can act as effective inhibitors for the HIV-1 viral protein.