Molecular modeling studies of 1,2,4-triazine derivatives as novel h-DAAO inhibitors by 3D-QSAR, docking and dynamics simulations

摘要

Human D -amino acid oxidase (h-DAAO) can effectively act on D -serine, which has been actively explored as a novel therapeutic target for treating schizophrenia. In this study, 37 h-DAAO inhibitors based on a 6-hydroxy-1,2,4-triazine-3,5(2 H ,4 H )-dione scaffold were obtained to construct the optimal comparative molecular field analysis (CoMFA, q ~(2) = 0.613, r ~(2) = 0.966) and comparative molecular similarity index analysis (CoMSIA, q ~(2) = 0.669, r ~(2) = 0.985) models. The results indicate that the models have good predictability and strong stability. Furthermore, contour maps of the three-dimensional quantitative structure–activity relationship (3D-QSAR) revealed the relationships between the structural features and inhibitory activity. A total of nine new h-DAAO inhibitors were designed, which exhibited good predicted pIC _(50) values. Through molecular docking and molecular dynamics simulation, four essential residues ( i.e. , Gly313, Arg283, Tyr224 and Tyr228) were considered to interact with the inhibitor. The hydrogen bonds produced by the triazine structure with protein and the hydrophobic interactions with the residues ( i.e. , Leu51, His217, Gln53 and Leu215) play an important role in the stability of the inhibitor at the binding site of the protein. Additionally, the compounds D1 , D3 and D8 , with higher predicted activities, were selected by ADME and bioavailability prediction. The present study could offer a reliable theoretical basis for future structural optimisation, design and synthesis of effective antipsychotics.