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

Abstract

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.

Authors:
 [1]; ORCiD logo [2];  [3];  [2];  [4];  [5];  [2];  [1];  [1];  [2]; ORCiD logo [6]
  1. Schrodinger, New York, NY (United States)
  2. UCSF, San Francisco, CA (United States)
  3. Stanford Univ., Stanford, CA (United States). SLAC National Accelerator Lab
  4. Stanford Univ., Stanford, CA (United States)
  5. Univ. Paris-Saclay, Palaiseau (France)
  6. UCSF, San Francisco, CA (United States); Stanford Univ., Stanford, CA (United States). SLAC National Accelerator Lab
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1493576
Grant/Contract Number:  
AC02-76SF00515; NNF15OC0015268; STC-1231306; LFR-17-476732; GM123159; GM124149
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 24; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

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., and van den Bedem, Henry. qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps. United States: N. p., 2018. Web. doi:10.1021/acs.jmedchem.8b01292.
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. qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps. United States. https://doi.org/10.1021/acs.jmedchem.8b01292
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., and van den Bedem, Henry. Tue . "qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps". United States. https://doi.org/10.1021/acs.jmedchem.8b01292. https://www.osti.gov/servlets/purl/1493576.
@article{osti_1493576,
title = {qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps},
author = {van Zundert, Gydo C. P. and Hudson, Brandi M. and de Oliveira, Saulo H. P. and Keedy, Daniel A. and Fonseca, Rasmus and Heliou, Amelie and Suresh, Pooja and Borrelli, Kenneth and Day, Tyler and Fraser, James S. and van den Bedem, Henry},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.8b01292},
journal = {Journal of Medicinal Chemistry},
number = 24,
volume = 61,
place = {United States},
year = {2018},
month = {11}
}

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