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.