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Multi-Conformer Ensemble Docking to Difficult Protein Targets

Journal Article · · Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry
DOI:https://doi.org/10.1021/jp506511p· OSTI ID:1265909
 [1];  [2];  [2];  [2]
  1. Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Kentucky, Lexington, KY (United States)
  2. Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
+ Show Author Affiliations
We investigate large-scale ensemble docking using five proteins from the Directory of Useful Decoys (DUD, dud.docking.org) for which docking to crystal structures has proven difficult. Molecular dynamics trajectories are produced for each protein and an ensemble of representative conformational structures extracted from the trajectories. Docking calculations are performed on these selected simulation structures and ensemble-based enrichment factors compared with those obtained using docking in crystal structures of the same protein targets or random selection of compounds. We also found simulation-derived snapshots with improved enrichment factors that increased the chemical diversity of docking hits for four of the five selected proteins. A combination of all the docking results obtained from molecular dynamics simulation followed by selection of top-ranking compounds appears to be an effective strategy for increasing the number and diversity of hits when using docking to screen large libraries of chemicals against difficult protein targets.
Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Organization:
DOE Office of Science; USDOE
Grant/Contract Number:
AC05-00OR22725
OSTI ID:
1265909
Journal Information:
Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry, Journal Name: Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry Journal Issue: 3 Vol. 119; ISSN 1520-6106
Publisher:
American Chemical SocietyCopyright Statement
Country of Publication:
United States
Language:
English

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Protein-Ligand Docking with Protein-based and Ligand-based Structure Activity Relationships posted_content January 2018
The TATA‐binding Protein DNA‐binding domain of eukaryotic parasites is a potentially druggable target journal October 2019
Principles and Overview of Sampling Methods for Modeling Macromolecular Structure and Dynamics journal April 2016
Computational study of HIV gp120 as a target for polyanionic entry inhibitors: Exploiting the V3 loop region journal January 2018
Computational methods in drug discovery journal January 2016
Small-molecule inhibitors identify the RAD52-ssDNA interaction as critical for recovery from replication stress and for survival of BRCA2 deficient cells journal July 2016

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