The Quasi-Bound State as a Predictor of Relative Binding Free Energy.

ABSTRACT: Relative binding free energy (ΔΔG_bind) predictions have become the main approach to evaluate the potency of a congeneric series of compounds. They are enabled by alchemical transformations coupled to free energy methods, tools that have become essential in drug design. Yet, they are computationally expensive and are limited to small compound sets and relatively simple transformations. The ever-increasing size of virtual screening databases demands faster methods to assess virtual hits. Here, we show that the structural robustness of protein-ligand complexes, measured as the free energy necessary to reach a quasi-bound state (ΔG_QB) by Dynamic Undocking (DUck), is well suited to detect outliers in the structure-activity continuum (i.e., activity cliffs), w

SUBMITTER: Serrano-Morras A 

PROVIDER: S-EPMC12164264 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature