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qFit-ligand reveals widespread conformational heterogeneity of drug-like molecules in X-ray electron density maps

Gydo C.P. van Zundert, View ORCID ProfileBrandi M. Hudson, View ORCID ProfileDaniel A. Keedy, View ORCID ProfileRasmus Fonseca, Amelie Heliou, Pooja Suresh, Kenneth Borrelli, View ORCID ProfileTyler Day, View ORCID ProfileJames S. Fraser, View ORCID ProfileHenry van den Bedem
doi: https://doi.org/10.1101/253419
Gydo C.P. van Zundert
1Schrödinger, New York, NY 10036, USA
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Brandi M. Hudson
2Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA 94158, USA
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Daniel A. Keedy
2Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA 94158, USA
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Rasmus Fonseca
3Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA.
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Amelie Heliou
4LIX, Ecole Polytechnique, CNRS, INRIA, Université Paris-Saclay, 91128, Palaiseau, France.
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Pooja Suresh
2Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA 94158, USA
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Kenneth Borrelli
1Schrödinger, New York, NY 10036, USA
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Tyler Day
1Schrödinger, New York, NY 10036, USA
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James S. Fraser
2Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA 94158, USA
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Henry van den Bedem
5SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA 94025 USA
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  • ORCID record for Henry van den Bedem
  • For correspondence: vdbedem@stanford.edu
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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.

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Posted January 25, 2018.
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qFit-ligand reveals widespread conformational heterogeneity of drug-like molecules in X-ray electron density maps
Gydo C.P. van Zundert, Brandi M. Hudson, Daniel A. Keedy, Rasmus Fonseca, Amelie Heliou, Pooja Suresh, Kenneth Borrelli, Tyler Day, James S. Fraser, Henry van den Bedem
bioRxiv 253419; doi: https://doi.org/10.1101/253419
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qFit-ligand reveals widespread conformational heterogeneity of drug-like molecules in X-ray electron density maps
Gydo C.P. van Zundert, Brandi M. Hudson, Daniel A. Keedy, Rasmus Fonseca, Amelie Heliou, Pooja Suresh, Kenneth Borrelli, Tyler Day, James S. Fraser, Henry van den Bedem
bioRxiv 253419; doi: https://doi.org/10.1101/253419

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