Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed to Reproduce Known Ligand Binding?

Wilfredo Evangelista Falcon; Sally R. Ellingson; Jeremy C. Smith; Jerome Baudry

doi:10.1021/acs.jpcb.8b11491

Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed to Reproduce Known Ligand Binding?

Wilfredo Evangelista Falcon, Sally R. Ellingson, Jeremy C. Smith, Jerome Baudry

Internal Medicine

Research output: Contribution to journal › Article › peer-review

71 Scopus citations

Abstract

Ensemble docking in drug discovery or chemical biology uses dynamical simulations of target proteins to generate binding site conformations for docking campaigns. We show that 600 ns molecular dynamics simulations of four G-protein-coupled receptors in their membrane environments generate ensembles of protein configurations that, collectively, are selected by 70 99% of the known ligands of these proteins. Therefore, the process of ligand recognition by conformational selection can be reproduced by combining molecular dynamics and docking calculations. Clustering of the molecular dynamics trajectories, however, does not necessarily identify the protein conformations that are most often selected by the ligands.

Original language	English
Pages (from-to)	5189-5195
Number of pages	7
Journal	Journal of Physical Chemistry B
Volume	123
Issue number	25
DOIs	https://doi.org/10.1021/acs.jpcb.8b11491
State	Published - Jun 27 2019

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society.

Funding

J.B. acknowledges the University of Alabama in Huntsville for support. J.B., J.C.S., and W.E.F. acknowledge support from the University of Tennessee, the LDRD program of ORNL, and SRE, the Cancer Research Informatics Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558).

Funders	Funder number
Oak Ridge National Laboratory
Laboratory Directed Research and Development
University of Tennessee
University of Kentucky Markey Cancer Center	P30CA177558
University of Kentucky Markey Cancer Center

ASJC Scopus subject areas

Physical and Theoretical Chemistry
Surfaces, Coatings and Films
Materials Chemistry

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10.1021/acs.jpcb.8b11491

Cite this

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title = "Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed to Reproduce Known Ligand Binding?",

abstract = "Ensemble docking in drug discovery or chemical biology uses dynamical simulations of target proteins to generate binding site conformations for docking campaigns. We show that 600 ns molecular dynamics simulations of four G-protein-coupled receptors in their membrane environments generate ensembles of protein configurations that, collectively, are selected by 70 99% of the known ligands of these proteins. Therefore, the process of ligand recognition by conformational selection can be reproduced by combining molecular dynamics and docking calculations. Clustering of the molecular dynamics trajectories, however, does not necessarily identify the protein conformations that are most often selected by the ligands.",

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Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed to Reproduce Known Ligand Binding? / Evangelista Falcon, Wilfredo; Ellingson, Sally R.; Smith, Jeremy C. et al.
In: Journal of Physical Chemistry B, Vol. 123, No. 25, 27.06.2019, p. 5189-5195.

Research output: Contribution to journal › Article › peer-review

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Ensemble Docking in Drug Discovery: How Many Protein Configurations from Molecular Dynamics Simulations are Needed to Reproduce Known Ligand Binding?

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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