CORCEMA evaluation of the potential role of intermolecular transferred NOESY in the characterization of ligand-receptor complexes

J Comput Aided Mol Des. 1996 Oct;10(5):361-71. doi: 10.1007/BF00124470.

Abstract

We report a theoretical characterization of the intermolecular transferred NOESY (inter-TrNOESY) between ligands and receptor macromolecules that bind reversibly, using a COmplete Relaxation and Conformational Exchange MAtrix (CORCEMA) theory developed in our laboratory. We examine the dependence of inter-TrNOESY on the dissociation constant, off-rate, ligand-to-receptor ratio, and distance variations between protons of interacting species within the complex. These factors are analyzed from simulations on two model systems: (i) neuraminidase complexed to a transition-state analogue; and (ii) thermolysin complexed to a leucine-based inhibitor. The latter case utilizes a three-state model of interaction to simulate the effect of hinge-bending motions on the inter-TrNOESY. Our calculations suggest a potential role for inter-TrNOESY (when observable) and CORCEMA analysis in properly docking the ligand within the active site, and in refining the conformation of the ligand-receptor (active-site) complex. These findings have implications on the structure-based design of ligands (e.g., inhibitors) reversibly binding to receptors (e.g., enzymes).

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Computer-Aided Design
  • Drug Design
  • Ligands
  • Macromolecular Substances
  • Magnetic Resonance Spectroscopy / methods*
  • Models, Chemical*
  • Molecular Structure
  • Neuraminidase / chemistry
  • Protons
  • Receptors, Cell Surface / chemistry*
  • Software*
  • Thermolysin / antagonists & inhibitors
  • Thermolysin / chemistry

Substances

  • Ligands
  • Macromolecular Substances
  • Protons
  • Receptors, Cell Surface
  • Neuraminidase
  • Thermolysin