Journal of Computer-Aided Molecular Design

, Volume 10, Issue 5, pp 361–371 | Cite as

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

  • Ernest V. Curto
  • Hunter N. B. Moseley
  • N. Rama Krishna
Research Papers

Summary

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).

Keywords

Conformational exchange Complete relaxation matrix CORCEMA Hinge-bending Transferred NOESY Structure-based drug design by NMR Ligand-receptor complexes 

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Copyright information

© ESCOM Science Publishers B.V 1996

Authors and Affiliations

  • Ernest V. Curto
    • 1
    • 2
  • Hunter N. B. Moseley
    • 1
    • 2
  • N. Rama Krishna
    • 1
    • 2
  1. 1.Department of Biochemistry and Molecular GeneticsThe University of Alabama at BirminghamBirminghamU.S.A.
  2. 2.Comprehensive Cancer CenterThe University of Alabama at BirminghamBirminghamU.S.A.

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