qFit-ligand reveals widespread conformational heterogeneity of drug-like molecules in X-ray electron density maps
Category
Published on
Type
posted-content
Author
Gydo CP van Zundert and Brandi M Hudson and Daniel A Keedy and Rasmus Fonseca and Amelie Heliou and Pooja Suresh and Kenneth Borrelli and Tyler Day and James S Fraser and Henry van den Bedem
Citation
Van Zundert, G.C. et al., 2018. qFit-ligand reveals widespread conformational heterogeneity of drug-like molecules in X-ray electron density maps. Available at: http://dx.doi.org/10.1101/253419.
Abstract
Proteins and ligands sample a conformational ensemble that governs molecular recognition, activity, and dissociation. In structure-based drug design, access to this conformational ensemble is critical to understand the balance between entropy and enthalpy in lead optimization. However, ligand conformational heterogeneity is currently severely underreported in crystal structures in the Protein Data Bank, owing in part to a lack of automated and unbiased procedures to model an ensemble of protein-ligand states into X-ray data. Here, we designed a computational method, qFit-ligand, to automatically resolve conformationally averaged ligand heterogeneity in crystal structures, and applied it to a large set of protein receptor-ligand complexes. We found that up to 29% of a dataset of protein crystal structures bound with drug-like molecules present evidence of unmodeled, averaged, relatively isoenergetic conformations in ligand-receptor interactions. In many retrospective cases, these alternate conformations were adventitiously exploited to guide compound design, resulting in improved potency or selectivity. Combining qFit-ligand with high-throughput screening or multi-temperature crystallography could therefore augment the structure-based drug design toolbox.
DOI
Funding
NSF-STC Biology with X-ray Lasers (NSF-1231306)
