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Ensemble Simulations and Experimental Free Energy Distributions: Evaluation and Characterization of Isoxazole Amides as SMYD3 Inhibitors

Journal Article · · Journal of Chemical Information and Modeling
 [1];  [1];  [1];  [2];  [3];  [2];  [1]
  1. University College London, London (United Kingdom)
  2. GlaxoSmithKline, Gunnels Wood Road, Stevenage (United Kingdom)
  3. GlaxoSmithKline, Collegeville, PA (United States)
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Optimization of binding affinities for ligands to their target protein is a primary objective in rational drug discovery. Herein, we report on a collaborative study that evaluates various compounds designed to bind to the SET and MYND domain-containing protein 3 (SMYD3). SMYD3 is a histone methyltransferase and plays an important role in transcriptional regulation in cell proliferation, cell cycle, and human carcinogenesis. Experimental measurements using the scintillation proximity assay show that the distributions of binding free energies from a large number of independent measurements exhibit non-normal properties. We use ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling) protocols to predict the binding free energies and to provide a detailed chemical insight into the nature of ligand-protein binding. Our results show that the 1-trajectory ESMACS protocol works well for the set of ligands studied here. Although one unexplained outlier exists, we obtain excellent statistical ranking across the set of compounds from the ESMACS protocol and good agreement between calculations and experiments for the relative binding free energies from the TIES protocol. ESMACS and TIES are again found to be powerful protocols for the accurate comparison of the binding free energies.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States); GlaxoSmithKline, Collegeville, PA (United States); University College London, London (United Kingdom)
Sponsoring Organization:
Engineering and Physical Sciences Research Council (EPSRC); European Union H2020; National Science Foundation (NSF); UK MRC Medical Bioinformatics; USDOE
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1981872
Journal Information:
Journal of Chemical Information and Modeling, Journal Name: Journal of Chemical Information and Modeling Journal Issue: 10 Vol. 62; ISSN 1549-9596
Publisher:
American Chemical SocietyCopyright Statement
Country of Publication:
United States
Language:
English

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
97 MATHEMATICS AND COMPUTING