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 existing inhibitors is an attractive approach for anticancer drug discovery.
Methods: We generated six types of independent models through structural based molecular docking study, threedimensional quantitative structure-activity relationship (3D-QSAR) study and 2D-QSAR approaches using different fingerprints including dendritic, linear, 2Dmolprint and radial.
Results and Discussion: Comparing the generated models showed that the hinge region hydrogen bond interaction with
amino acids ASP1206, MET1199 and LYS1150 in docking analysis and the hydrophobic interactions 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-diarylaminopyrimidine 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.