Molecular modelling studies of tricyclic triazinone analogues as potential PKC-θ inhibitors through combined QSAR, molecular docking and molecular dynamics simulations techniques

Abstract

Abstract Protein kinase C theta (PKC-θ), which can trigger dysregulation of the T cell pathway and consequently lead to immune diseases, is a highly promising target for immunosuppressive agents. To search for potential PKC-θ inhibitors with few side effects, the structure activity relationship (SAR) of 54 tricyclic triazinone analogues as PKC-θ inhibitors was systematically discussed and studied by combined QSAR, molecular docking and molecular dynamics (MD) simulation, and reliable CoMFA (q2 = 0.863, r2 = 0.988, rpred2 = 0.899) and CoMSIA (q2 = 0.824, r2 = 0.984, rpred2 = 0.835) models were established and assisted with the HQSAR and 2D-QSAR models. Several key resides, namely, Glu459, Val394, Leu511, Met458, Phe668 and Asp465 were identified by Surflex–dock. Based on contour maps analysis and the docking analysis, eight novel PKC-θ inhibitors (D1–D8) were designed. The 10-ns MD simulations of 54 and D8 revealed that the introduction of fluorine atoms or hydrophobic structures into the β strand domain under the glycine-rich loop favored the stabilization of the ligand binding with the receptor. The predictive non-toxic compound D7, which showed good activity, was selected by ADMET predictions. Additionally, to expand the molecular library of PKC-θ inhibitors, we screened the database from the ZINC library based on the pharmacophore and obtained four skeletons (G1–G4). These results provided strong guidance for the discovery and design of novel potential PKC-θ selective inhibitors.