Induced-Fit Docking Enables Accurate Free Energy Perturbation Calculations in Homology Models

Abstract

Homology models have been used for virtual screening and to understand the binding mode of a known active, however rare-ly have the models been shown to be of sufficient accuracy, comparable to crystal structures, to support free-energy perturba-tion (FEP) calculations. We demonstrate here that the use of an advanced induced-fit docking methodology reliably enables predictive FEP calculations on congeneric series across homology models ≥ 30% sequence identity. Further, we show that retrospective FEP calculations on a congeneric series of drug-like ligands is sufficient to discriminate between predicted binding modes. Results are presented for a total of 29 homology models for 14 protein targets, showing FEP results compa-rable to those obtained using experimentally determined crystal structures for 86% of homology models with template struc-ture sequence identities ranging from 30% to 50%. Implications for the use and validation of homology models in drug dis-covery projects are discussed, including the use of AlphaFold2 de novo structures.