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J Mol Graph Model. 2014 Apr;49:18-24. doi: 10.1016/j.jmgm.2014.01.002. Epub 2014 Jan 13.

Identification of p38α MAP kinase inhibitors by pharmacophore based virtual screening.

Author information

  • 1Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160 062, India.
  • 2Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160 062, India.
  • 3Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar (Mohali), Phase X, Sector-67, Punjab 160 062, India.
  • 4Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160 062, India. Electronic address: abhays@niper.ac.in.

Abstract

The p38α mitogen-activated protein (MAP) kinase plays a vital role in treating many inflammatory diseases. In the present study, a combined ligand and structure based pharmacophore model was developed to identify potential DFG-in selective p38 MAP kinase inhibitors. Conformations of co-crystallised inhibitors were used in the development and validation of ligand and structure based pharmacophore modeling approached. The validated pharmacophore was utilized in database screening to identify potential hits. After Lipinski's rule of five filter and molecular docking analysis, nineteen hits were purchased and selected for in vitro analysis. The virtual hits exhibited promising activity against tumor necrosis factor-α (TNF-α) with 23-98% inhibition at 10μM concentration. Out of these seven compounds has shown potent inhibitory activity against p38 MAP kinase with IC50 values ranging from 12.97 to 223.5nM. In addition, the toxicity study against HepG2 cells was also carried out to confirm the safety profile of identified virtual hits.

Copyright © 2014 Elsevier Inc. All rights reserved.

KEYWORDS:

Cytotoxicity; Molecular docking; Pharmacophore modeling; Virtual screening; p38 MAP kinase

[PubMed - indexed for MEDLINE]
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