Free Energy Calculation Guided Virtual Screening of Synthetically Feasible Ligand R-Group and Scaffold Modifications: An Emerging Paradigm for Lead Optimization

Abstract Virtual screening of small-molecule collections has become a widespread practice both in academic laboratories and in pharmaceutical companies to rapidly and inexpensively identify small molecules which bind to the intended target with sufficient affinity to facilitate initiation of a drug discovery project. However, this approach of computationally evaluating very large numbers of small molecules, and then selecting a small subset of these for additional experimental prosecution is seldom employed in the lead optimization phase of drug discovery project. Recent work enabling programmatic enumeration of the synthetically tractable idea space around the most promising lead molecules when appropriately combined with high-accuracy protein–ligand binding free energy calculations appears poised to allow this emerging paradigm to make great contributions to lead optimization.