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

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

Author information

1
Biomedical Sciences Program, University of California San Diego, La Jolla, California 92093-0365, USA.

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.

PMID:
19882751
PMCID:
PMC2950069
DOI:
10.1002/jmr.989
[Indexed for MEDLINE]
Free PMC Article

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