Combined molecular dynamics, STD-NMR, and CORCEMA protocol yields structural model for a UDP-galactopyranose mutase-inhibitor complex

Bioorg Med Chem Lett. 2015 Mar 15;25(6):1284-7. doi: 10.1016/j.bmcl.2015.01.044. Epub 2015 Jan 28.

Abstract

UDP-galactopyranose mutase (UGM) is an enzyme involved in the biosynthesis of the Mycobacterium tuberculosis cell wall, and is essential for the growth and survival of the organism. A micromolar inhibitor developed by tetrafluorination of the UGM substrate has been previously studied by saturation transfer difference (STD) NMR spectroscopy. To elucidate the bioactive conformation of the inhibitor bound to UGM, we employ molecular dynamics (MD) simulations to construct a structural model. The MD model is subsequently validated by a good fit between experimental and theoretical STD effects, the latter calculated by a complete relaxation and conformational exchange matrix (CORCEMA) analysis. This structural model is used to explain the relative binding affinities of the inhibitor and the parent substrate.

Keywords: CORCEMA; MD simulations; Saturation transfer difference; Structural model; UGM–inhibitor complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Intramolecular Transferases / antagonists & inhibitors*
  • Intramolecular Transferases / metabolism
  • Klebsiella pneumoniae / enzymology
  • Magnetic Resonance Spectroscopy
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Structure, Tertiary

Substances

  • Enzyme Inhibitors
  • Intramolecular Transferases
  • UDP-galactopyranose mutase