Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Chem Biol Drug Des. 2012 Jan;79(1):84-91. doi: 10.1111/j.1747-0285.2011.01250.x. Epub 2011 Nov 8.

3D-QSAR and molecular docking studies on substituted isothiazole analogs as inhibitors against MEK-1 kinase.

Author information

  • 1School of Chemistry, University of Hyderabad, Hyderabad, Andhra Pradesh, India.

Abstract

MEK-1 and MEK-2 are dual-specificity kinases and important components in the mitogen-activated protein kinase pathway. These enzymes are crucial for normal cell survival and are also expressed in several types of cancers, making them important targets for drug design. We have applied an integrated in silico approach that combines comparative molecular field analysis, comparative molecular similarity indices analysis, and molecular docking to study the structural determinants for the recognition of substituted isothiazole analogs as allosteric inhibitors against MEK-1 kinase. The best 3D-QSAR models for comparative molecular field analysis and comparative molecular similarity indices analysis were selected based on statistical parameters. 3D contour maps suggested that bulky or long-chain substitutions at the X position on the core part decrease the inhibitory activity, and the presence of a hydrogen bond donor substitution enhances the activity. The bulky and electronegative substitutions at the Y position on the core part enhance the activity of the inhibitors. Molecular docking studies reveal a large and hydrophobic pocket that accommodates the Y substitution and a polar pocket that accommodates substitutions on the X position and forms hydrogen bonding interactions with MEK-1 kinase. The results of the 3D-QSAR analysis corroborate with the molecular docking results, and our findings will serve as a basis for further development of better allosteric inhibitors of MEK-1 kinase against several cancers.

© 2011 John Wiley & Sons A/S.

PMID:
21967481
[PubMed - indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for Blackwell Publishing
    Loading ...
    Write to the Help Desk