Investigation of the noncovalent binding mode of covalent proteasome inhibitors around the transition state by combined use of cyclopropylic strain-based conformational restriction and computational modeling

J Med Chem. 2013 Jul 25;56(14):5829-42. doi: 10.1021/jm400542h. Epub 2013 Jul 9.

Abstract

To develop potent covalent inhibitors, the noncovalent interactions around the transition state to form covalent bonding should be optimized because the potency of the inhibitor can be depending on the energy of the transition state. Here, we report an efficient analysis of the noncovalent binding mode of a potent covalent proteasome inhibitor 3a around the transition state by a combined use of the chemical approach, i.e., the cyclopropylic strain-based conformational restriction, and the computational docking approach. Furthermore, we calculated the binding energy of a series of salinosporamide derivatives in the predicted noncovalent complex around the transition state with the simulation model of proteasome constructed in this study, which was well correlated to their pIC50. Thus, the proposed docking methods to predict the noncovalent binding mode around the transition state of covalent inhibitors will be helpful toward the development of covalent inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation
  • Crystallography, X-Ray
  • Models, Molecular
  • Molecular Conformation
  • Molecular Docking Simulation
  • Proteasome Inhibitors / chemical synthesis*
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Proteasome Inhibitors