Structural and Energetic Analysis of Lenacapavir Binding to Human Serum Albumin: A Computational Study Using Docking, Molecular Dynamics, and MMPBSA/MMGBSA

ABSTRACT Human immunodeficiency virus (HIV) remains one of the deadliest pandemics, targeting white blood cells and weakening the immune system. Lenacapavir (LEN), a long‐acting HIV‐1 capsid inhibitor, has shown remarkable efficacy when administered via subcutaneous injection. Since injectable drugs interact with blood proteins, understanding these interactions is crucial for optimizing pharmacokinetics and therapeutic efficacy. Human serum albumin (HSA), the most abundant blood protein, plays a key role in drug transportation, influencing the distribution and activity of LEN. In this study, we investigate the molecular binding of LEN to HSA using molecular docking, molecular dynamics (MD) simulations, MMPBSA and MMGBSA free energy calculations, and density functional theory (DFT). Docking results reveal that LEN preferentially binds to HSA domains I and III with a binding affinity of −10.77 kcal/mol. To capture the dynamic nature of the interactions, 200 ns MD simulations were performed, revealing stable complex formation through RMSD, RMSF, radius of gyration (Rg), clustering, PCA, and hydrogen bonding analysis. Free energy calculations (MMGBSA/MMPBSA) indicate that LEN binding is thermodynamically favorable and predominantly driven by van der Waals interactions. Per‐residue energy decomposition highlights key residues (ILE:142, ARG:145, HIS:146, ARG:186, ALA:194, GLN:459, and LYS:519) contributing to the binding affinity. Additionally, DFT calculations reveal LEN's electronic properties, including HOMO‐LUMO energy levels and electrostatic potential, offering atomic‐level insights into its interaction with HSA. Overall, our study reveals that LEN binds stably and energetically favorably to key residues of human serum albumin, providing mechanistic insights that may aid in optimizing HIV drug delivery and efficacy.