Insights into the structural requirements of PKCζ inhibitors as potential anti-arthritis agents based on 3D-QSAR, homology modeling and docking approach

Abstract

Abstract Protein Kinase C ζ (PKCζ) has emerged as a promising novel drug target for the treatment of arthritis. A series of isoquinoline PKCζ inhibitors were analyzed through CoMFA, CoMSIA, homology modeling, and molecular docking to obtain insights into the structural requirements of PKCζ inhibitors. To our best knowledge, this work is the first report on 3D-QSAR modeling of PKCζ inhibitors. The constructed CoMFA (q2\xa0=\xa00.578, r2\xa0=\xa00.89, r2predr2pred\xa0=\xa00.756) and CoMSIA (q2\xa0=\xa00.758, r2\xa0=\xa00.983, r2pred\xa0=\xa00.753) models showed a good statistical robustness and a high external predictability. With a reliable template structure (4DC2), a homology model of PKCζ was built and the Ramachandran plot indicated that the above homology model was acceptable. PKCζ inhibitors were docked into the binding site of the homology model of PKCζ to get their binding mode. The structural requirements for PKCζ inhibition were highlighted in our results, which may contribute to the development of novel PKCζ inhibitors.