Accurate and reliable protein-ligand binding free energy calculations are playing an increasingly important role in small molecule drug discovery. However, these calculations only work well for the ligands binding to the same conformation of the protein and are inaccurate when large conformational changes in the protein pocket are induced upon ligand binding or upon chemical modifications in the ligand. In this presentation, I am going to introduce a unique free energy perturbation approach that allows accurate and efficient calculation of protein conformational free energy differences via a nonphysical alchemical pathway. Applications of this method on two retrospective drug discovery programs are presented to showcase possible ways for ligands to improve binding affinity utilizing free energy differences among multiple possible protein conformations: in Abl tyrosine kinase by avoiding a high protein reorganization free energy, and in heat-shock protein 90 (HSP90) by offsetting a low protein reorganization free energy with more potential binding site interactions.

Quantitatively accounting for protein reorganization free energies and applications in drug discovery

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ACS Spring 2023

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