Free energy calculations are revolutionizing how early-stage drug-discovery campaigns are undertaken. Robust free energy methods can rapidly provide on-target potency predictions to identify promising chemical matter for synthesis, inspiring further rounds of ideation and optimization. Ligand binding free energies can also be explicitly computed within other protein structures to ensure that promising designs will be sufficiently weak in their binding to key off-targets. Free energy methods that perturb protein residues have been used to predict the change in ligand affinities in the presence of clinically-relevant resistance mutations and to predict protein-protein binding affinities, usually in the context of modeling antigen-antibody interactions, assembly of molecular machines, or cell-cell recognition events. Here, we demonstrate the ability of protein free energy methods to elucidate ligand binding activities for large families of off-targets. We show how predictions based on a judicious selection of residues to perturb in protein free energy calculations can be a surrogate for explicit binding affinity measurements across a large panel of proteins. This strategy couples ligand free energy calculations with protein free energy calculations to simultaneously find promising chemical matter and de-risk for off-target liabilities. Designs with optimal potency and selectivity profiles can be rapidly identified and prioritized for synthesis, thereby accelerating drug discovery timelines.

De-risking off-target liabilities with protein free energy methods

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.