Molecular Docking, 3D-QSAR, Fingerprint-Based 2D-QSAR, Analysis of Pyrimidine, and Analogs of ALK (Anaplastic Lymphoma Kinase) Inhibitors as an Anticancer Agent

Background: ALK inhibitors have become a plausible option for anticancer therapy with the availability of several FDA-approved molecules and clinical trial candidates. Hence, the design of new ALK inhibitors using computational molecular docking studies on the existing inhibitors, is an attractive approach for anticancer drug discovery. Methods: We generated six types of independent models through structural based molecular docking study, three-dimensional quantitative structure-activity relationship (3D-QSAR) study, and 2DQSAR approaches using different fingerprints, such as dendritic, linear, 2D molprint, and radial. Results: Comparison of the generated models showed that the hinge region hydrogen bond interacted with amino acids ASP1206, MET1199, and LYS1150 in docking analysis and the hydrophobic interacted with amino acids GLU1210, ARG1209, SER1206, and LYS1205 residues are responsible for the ALK inhibition. In the 3D-QSAR study, the hydrogen bond donor features of 2,4- diaryl aminopyrimidine substituents, isopropyl phenyl ring groups in hydrophobic features, and electron-withdrawing groups matched the generated contour plots. The 2D-QSAR fingerprint studies indicated that higher potency was associated with the 2-hydroxy-5-isopropyl benzamide functional group and substituted phenylamine at the second position of the pyrimidine group. Conclusion: We conclude that the incorporation of these functional groups in the design of new molecules may result in more potent ALK inhibitors.