Including receptor flexibility and induced fit effects into the design of MMP-2 inhibitors

J Mol Recognit. Mar-Apr 2010;23(2):173-82. doi: 10.1002/jmr.989.

Abstract

Matrix metalloproteinases (MMPs) comprise a class of flexible proteins required for normal tissue remodeling. Overexpression of MMPs is associated with a wide range of pathophysiological processes, including vascular disease, multiple sclerosis, Alzheimer's disease, and cancer. Nearly all MMP inhibitors have failed in clinical trials, in part due to lack of specificity. Due to the highly dynamic molecular motions of the MMP-2 binding pockets, the rational drug design of MMP inhibitors has been very challenging. To address these challenges, in the current study we combine computer docking with molecular dynamics (MD) simulations in order to incorporate receptor-flexibility and induced-fit effects into the drug-design process. Our strategy identifies molecular fragments predicted to target multiple MMP-2 binding pockets.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Drug Design*
  • Humans
  • Ligands*
  • Matrix Metalloproteinase 2 / chemistry*
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase Inhibitors*
  • Models, Molecular
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Pliability
  • Protein Binding
  • Protein Conformation

Substances

  • Ligands
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinase 2