He, Michael, Lee, Patrick and Sweeney, Zachary (2014) Promiscuity and the Conformational Rearrangement of Drug-like Molecules: Insight from the Protein Data Bank. ChemMedChem, 10. ISSN 1860-7187

Abstract

Selectivity is a central aspect of lead optimization during the drug discovery process. It is commonly believed that selectivity is a function of small molecule conformational flexibility, and some inhibitors are known to conformationally adapt to optimally interact with different proteins. Consequently, medicinal chemists often try to reduce molecular flexibility to improve selectivity. To further investigate the relationship between polypharmacology and conformational flexibility, we mined the Protein Data Bank (PDB) to construct a manually curated dataset of 100 pharmaceutically relevant ligands that: a) have been crystallized in more than one protein target and b) bind each co-crystallized receptor with similar in vitro affinities. After analyzing the individual molecular conformations of the 100 compounds, we found that 59 compounds bound to different protein targets without significantly changing conformation (RMSD < 0.45), suggesting that there is no distinct correlation between conformational flexibility and polypharmacology within our dataset. Compounds that were crystallized in similar proteins (binding pocket homology (BPH) > 80%) were less likely to adjust conformation when binding. Highly ligand efficient (LigE > 0.32) compounds with 5 or fewer rotatable bonds were also less likely to adjust conformation. We were unable to identify a significant relationship within our dataset between the likelihood of conformational change and either molecular weight, total polar surface area, or the number of ring structures in the ligand.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/22541