Balancing Enthalpy and Entropy in Inhibitors 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 drug 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. Microseconds of 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 balancing in the thermodynamic driving force of different inhibitors. The binding of inhibitors in monomeric form is entropy-driving, in which the solvation entropy from the binding-induced water restraints play a key role, while the binding of inhibitors in dimeric form is enthalpy-driving, due to the promiscuous PSMA-inhibitor interactions. This insights about the molecular driving force of protein-ligand binding offer valuable guidance for rational drug design targeting PSMA.