Computational Studies Of The Inhibitors Of The Tumor Proteins For Chk1,mTOR And CD38

Computer aided drug design (CADD) played an important role in the drug design. In this paper, the CADD was applied to the inhibitors of checkpoint kinases 1 (Chk1),mTOR and CD38 to study the QSAR, and provide theoretical support for the design of the lead compounds. First, 40 GNE-783 analogues of the Chk1 protein were investigated using CADD simulations. Chkl is an important serine/threonine kinase, most cancer cells through the S and G2-M level repair themselves. Chk1 inhibition can disable S and G2 checkpoint, prevent cancer cells to repair, result in mitotic division problems, and even cell death or apoptosis,and thus profound research significance. The study shown that the most comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis results with q2 = 0.726, r2 = 0.918 and q2 = 0.532, r2 = 0.950, respectively. Molecular docking results shown the important residues between ligand and receptor, such as Glu85, Cys87, Lys38,Gly90, etc., molecular dynamics simulation verify the conclusion of the molecular docking. In addition, computational studies of the urea-morpholine ring derivatives as the Mtor inhibitors.Which CoMFA and CoMSIA shows q2 = 0.750, r2 = 0.931 and q2 = 0.745,r2 = 0.927,respectively. Docking studies shown that the morpholine ring paly an important role of the inhibitors activities, the other important residues were Va1882, Lys802, Lys808, Ser806, etc.Finally, 47 thiazolequinoline derivatives as CD38 inhibitors were studied by computer simulation, CoMFA and CoMSIA results show that q2 = 0.790, r2 = 0.967 and q2 = 0.662, r2 =0.915, respectively. Moreover, Topomer CoMFA model was used to verify the exactness of two models, the statistical results showed q2 = 0.662, r2 = 0.915. The contour maps showed the hydrophobic and electrostatic fields were critical to the biological activity of these inhibitors. Molecular docking show that the hydrophobic/lipophilic interactions formed by the quinazoline ring and the residues Trp189 were beneficial to activity. These conclusions not only provide guidance for the design of highly selective and highly active drugs, but also can be used to predict the inhibitory activity of new compounds and reduce the cycle of drug synthesis.