Alchemical absolute protein–ligand binding free energies for drug design

• DOI: 10.1039/d1sc03472c
• Publication Date: 2021-09-24T14:42:33Z
• Authors: Y. Khalak; G. Tresadern; M. Aldeghi; H. M. Baumann; D. L. Mobley; B. L. de Groot; V. Gapsys
• Keywords: 0301 basic medicine; 500; 540; 01 natural sciences; 3. Good health; Medicinal and Biomolecular Chemistry; Chemistry; 03 medical and health sciences; Chemical sciences; Chemical Sciences; 0103 physical sciences

The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods drug discovery. Accurately assessing absolute energies, although highly desired, remains a challenging endeavour, mostly limited to small model cases. Here, we demonstrate accurate first principles based estimates for 128 pharmaceutically relevant targets. We use novel rigorous method generate ensembles ligand its decoupled state. Not only do deliver affinity estimates, but they also provide detailed physical insight into structural determinants binding. identify subtle rotamer rearrangements between apo and holo states protein that are crucial When compared calculations, obtaining energies is considerably more large part due need explicitly account In this work present several approaches obtain state ΔG thus outlining protocols prospective application