Structure-based 3D-QSAR models and dynamics analysis of novel N-benzyl pyridinone as p38α MAP kinase inhibitors for anticytokine activity

Zaheer Ul-Haq; Waqasuddin Khan; Syeda Rehana Zia; Sadaf Iqbal

doi:10.1016/j.jmgm.2012.02.003

Structure-based 3D-QSAR models and dynamics analysis of novel N-benzyl pyridinone as p38α MAP kinase inhibitors for anticytokine activity

J Mol Graph Model. 2012 Jun:36:48-61. doi: 10.1016/j.jmgm.2012.02.003. Epub 2012 Mar 6.

Authors

Zaheer Ul-Haq¹, Waqasuddin Khan, Syeda Rehana Zia, Sadaf Iqbal

Affiliation

¹ Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center, for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan. [email protected]

PMID: 22534481
DOI: 10.1016/j.jmgm.2012.02.003

Abstract

A novel series of anticytokine N-benzyl pyridinone derivatives that targets p38α MAP kinase has been analyzed by utilizing a combination of molecular modeling techniques. Statistically significant structure-based 3D-QSAR models were generated for both CoMFA and CoMSIA, and validated through acceptable predictive ability to support both internal and external set of compounds. Structural changes within the protein key backbone residues (Met109 and Gly110), DFG loop position, and side chain movements (Lys53 and Asn114) as resulted by different substituents on these inhibitors were also examined by molecular dynamics simulation. The protocol applied in this study could be helpful to rationalize potent compounds with better inhibitory activity and selectivity profiles against p38α MAP kinase.

MeSH terms

Humans
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 14 / chemistry*
Molecular Dynamics Simulation*
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Quantitative Structure-Activity Relationship*

Substances

Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase 14