qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps

van Zundert, Gydo C. P.; Hudson, Brandi M.; de Oliveira, Saulo H. P.; Keedy, Daniel A.; Fonseca, Rasmus; Heliou, Amelie; Suresh, Pooja; Borrelli, Kenneth; Day, Tyler; Fraser, James S.; van den Bedem, Henry

doi:10.1021/acs.jmedchem.8b01292

Title: qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps

Journal Article · 20 November 2018 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/acs.jmedchem.8b01292 · OSTI ID:1493576

van Zundert, Gydo C. P. ^[1];

^[2]; de Oliveira, Saulo H. P. ^[3]; Keedy, Daniel A. ^[2]; Fonseca, Rasmus ^[4]; Heliou, Amelie ^[5]; Suresh, Pooja ^[2]; Borrelli, Kenneth ^[1]; Day, Tyler ^[1]; Fraser, James S. ^[2];

^[6]

Schrodinger, New York, NY (United States)
UCSF, San Francisco, CA (United States)
Stanford Univ., Stanford, CA (United States). SLAC National Accelerator Lab
Stanford Univ., Stanford, CA (United States)
Univ. Paris-Saclay, Palaiseau (France)
UCSF, San Francisco, CA (United States); Stanford Univ., Stanford, CA (United States). SLAC National Accelerator Lab

Here, 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. In an analysis of the cancer related BRD4 domain, we found that up to 29% 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 multitemperature crystallography could therefore augment the structure-based drug design toolbox.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515; NNF15OC0015268; STC-1231306; LFR-17-476732; GM123159; GM124149

OSTI ID:: 1493576

Journal Information:: Journal of Medicinal Chemistry, Vol. 61, Issue 24; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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