Molecular Docking, 3D-QSAR, Fingerprint-Based 2D-QSAR Analysis of Pyrimidine Analogues of ALK Inhibitors As an Anticancer Agent
Posted: 11 Feb 2020
Date Written: February 7, 2020
In recent years there are several FDA approved molecules and clinical trial candidates of ALK inhibitors make it an attractive target for anticancer therapy. Hence the designing of ALK inhibitor would be an attractive approach for anticancer drug discovery. With this intention, we wanted to understand the already reported molecules through computational modeling study. We performed molecular docking study from already reported molecules so that with the use of this information we come up with the design of new molecules. Six types of independent models were generated through computational modeling study approaches such as structural based molecular docking study, three-dimensional quantitative structure-activity relationship (3D-QSAR) study and 2D-QSAR approaches using different fingerprints dendritic, linear, 2Dmolprint & radial. After comparing the generated models we found that the hinge region hydrogen bond interaction with amino acid ASP 1206, MET 1199 and LYS 1150 in docking analysis, the hydrophobic interactions with amino acid GLU 1210, ARG 1209, SER 1206 & LYS 1205 residues responsible for the ALK inhibition activity. In the 3D-QSAR study the hydrogen bond donor features of 2,4-Diaminopyrimidine substituents, isopropyl phenyl ring groups in hydrophobic features and electron withdrawing groups matched the contour plots generated. The 2D-QSAR fingerprint studies represent that the dendritic models generated with the best regression value showed by the 2-hydroxy-5-isopropyl benzamide functional group, and substituted phenylamine at the second position of pyrimidine which contributes towards the higher activity. So we conclude that the incorporation of the above-mentioned features in the design of molecules may result in a better activity.
Keywords: molecular docking, 3-d QSAR, ALK, fingerprint
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