Elucidating the molecular interactions between statins and P-glycoprotein: insights from molecular docking and dynamics simulations

P-glycoprotein (P-gp) substantially affects the pharmacokinetics and effectiveness of several medicines, including statins, by facilitating their efflux. This study employed computational methods to systematically examine the binding mechanisms, conformational dynamics, and binding affinities of nine statin compounds with human P-gp. Molecular docking demonstrated that seven statins effectively attached to the zosuquidar-defined binding site, with atorvastatin displaying the highest docking score. Subsequent molecular dynamics (MD) simulations revealed that statin binding stabilised P-gp, diminishing backbone flexibility and inhibiting long-range correlated motions, as indicated by decreased RMSD and RMSF values and modified dynamics in cross-correlation and principal component analysis. MM/PBSA binding free energy calculations indicated atorvastatin as the most potent binder, succeeded by cerivastatin and simvastatin. Energy decomposition and hydrogen bond analysis revealed that crucial residues (Tyr950, Gln946, His61, and Glu875) are essential for binding stability due to enduring hydrogen bonds and robust electrostatic interactions. Hydrophobic interactions with residues such as Leu65 and Gln347 augmented binding affinity. These findings clarify the molecular factors influencing statin–P-gp interactions and offer insights into the structure–activity link that regulates binding affinity and conformational stability. The results provide a basis for developing statins with enhanced P-gp binding characteristics, potentially augmenting their therapeutic effectiveness and pharmacokinetic profiles.