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

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.