Prediction of Drug–Target Binding Kinetics by Comparative Binding Energy Analysis

A growing
consensus is emerging that optimizing the drug–target
affinity alone under equilibrium conditions does not necessarily translate
into higher potency in vivo and that instead binding kinetic parameters
should be optimized to ensure better efficacy. Therefore, in silico
methods are needed to predict the kinetic parameters and the mechanistic
determinants of drug–protein binding. Here we demonstrate the
application of COMparative BINding Energy (COMBINE) analysis to derive
quantitative structure–kinetics relationships (QSKRs) for the
dissociation rate constants (koff) of
inhibitors of heat shock protein 90 (HSP90) and HIV-1 protease. We
derived protein-specific scoring functions by correlating koff rate constants with a subset of weighted
interaction energy components determined from the energy-minimized
structures of drug–protein complexes. As the QSKRs derived
for these sets of chemically diverse compounds have good predictive
ability and provide insights into important drug–protein interactions
for optimizing koff, COMBINE analysis
offers a promising approach for binding kinetics-guided lead optimization.