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Title: Application of the ESMACS Binding Free Energy Protocol to a Multi-Binding Site Lactate Dehydogenase A Ligand Dataset

Journal Article · · Advanced Theory and Simulations
ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [2]; ORCiD logo [2]; ORCiD logo [3]
  1. University College London (United Kingdom)
  2. Janssen Research & Development, Turnhoutseweg, Beerse (Belgium)
  3. University College London (United Kingdom); University of Amsterdam (Netherlands)
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Over the past two decades, the use of fragment-based lead generation has become a common, mature approach to identify tractable starting points in chemical space for the drug discovery process. This approach naturally involves the study of the binding properties of highly heterogeneous ligands. Such datasets challenge computational techniques to provide comparable binding free energy estimates from different binding modes. The performance of a range of statistically robust ensemble-based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent), is evaluated. Ligands designed to target two binding pockets in the lactate dehydogenase, a target protein, which vary in size, charge, and binding mode, are studied. When compared to experimental results, excellent statistical rankings are obtained across this highly diverse set of ligands. In addition, three approaches to account for entropic contributions are investigated: 1) normal mode analysis, 2) weighted solvent accessible surface area (WSAS), and 3) variational entropy. Normal mode analysis and WSAS correlate strongly with each other—although the latter is computationally far cheaper—but do not improve rankings. Variational entropy corrects exaggerated discrimination of ligands bound in different pockets but creates three outliers which reduce the quality of the overall ranking.

Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)
Sponsoring Organization:
USDOE Office of Science (SC); H2020 Future and Emerging Technologies; H2020 Development; MRC Biomedical Informatics; National Science Foundation (NSF)
Grant/Contract Number:
AC05-00OR22725
OSTI ID:
2469828
Journal Information:
Advanced Theory and Simulations, Journal Name: Advanced Theory and Simulations Journal Issue: 1 Vol. 3; ISSN 2513-0390
Publisher:
WileyCopyright Statement
Country of Publication:
United States
Language:
English

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
binding free energy calculations
fragment-based drug design
molecular dynamics
molecular mechanics Poisson–Boltzmann surface area (MMPBSA)
science & technology