Balancing enthalpy and entropy in inhibitor binding to the prostate-specific membrane antigen (PSMA)

Abstract

Understanding the molecular mechanism of inhibitor binding to prostate-specific membrane antigen (PSMA) is of fundamental importance for designing targeted drugs for prostate cancer. Here we designed a series of PSMA–targeting inhibitors with distinct molecular structures, which were synthesized and characterized using both experimental and computational approaches. Microsecond molecular dynamics simulations revealed the structural and thermodynamic details of PSMA–inhibitor interactions. Our findings emphasize the pivotal role of the inhibitor's P1 region in modulating binding affinity and selectivity and shed light on the binding-induced conformational shifts of two key loops (the entrance lid and the interface loop). Binding energy calculations demonstrate the enthalpy–entropy balance in the thermodynamic driving force of different inhibitors. The binding of inhibitors in monomeric form is entropy-driven, in which the solvation entropy from the binding-induced water restraints plays a key role, while the binding of inhibitors in dimeric form is enthalpy-driven, due to the promiscuous PSMA–inhibitor interactions. These insights into the molecular driving force of protein–ligand binding offer valuable guidance for rational drug design.