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(2H,4H)-dione scaffold were obtained to construct the optimal comparative molecular field analysis (CoMFA, q 2 ¼ 0.613, r 2 ¼ 0.966) and comparative molecular similarity indexThe 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.
The forced expression of phosphoinositide 3-kinase d (PI3Kd) in B cells was found to be oncogenic, rendering PI3Kd an attractive drug target for chronic lymphocytic leukaemia. This study aimed to systemically explore the interaction mechanism of novel quinazolinone scaffold-based derivatives as PI3Kd inhibitors using 3D-QSAR, molecular docking, pharmacophore model and molecular dynamics (MD) simulations. The 3D-QSAR models CoMFA, CoMSIA and Topomer CoMFA were established to discover critical structural factors affecting PI3Kd inhibitory activity. The models showed suitable reliabilities (q 2 0.741, 0.712 and 0.711) and predictive abilities (r pred 2 0.851, 0.738 and 0.828, respectively).Contour maps indicated that the bioactivity of PI3Kd inhibitor was affected most by electrostatic and hydrophobic fields. The Surflex-Dock and pharmacophore model result showed that enhancing the Hbond interaction of the key substituents around the 2-and 4-positions of pyrimidine with Glu826, Val828 and Asp911, as well as the electrostatic interactions of substituents around the 3-position of benzene with Ser831, Asp832 and Asn836, significantly affected the improvement in the activity and stability of the inhibitor. Based on these results, 10 novel PI3Kd inhibitors with higher predicted activity and binding affinity were designed by introducing the heterocycles pyrrolopyridine or purine. 10 ns MD simulations further study the stable docking conformation of designed compounds, which showed strong hydrogen bond interactions with key residues Ser831 and Asp832 in a propeller-like fashion.These results provided strong guidance for the discovery and optimization of novel potent PI3Kd selective inhibitors.
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