Theoretical and Experimental Investigations for Identification of Anaphylactic Lymphoma Kinase inhibitors

The ALK tyrosine kinase receptor is a promising target in lung cancer. To estimate ALK-TK inhibitory activity, we used QSAR modeling on heterocyclic compounds with varied structures and a large dataset of 1329 chemicals experimentally reported for anticancer activity against ALK-TK. The developed QSAR model meets various validation criteria, such as R2 = 0.79, Q2LOO = 0.78, Q2LMO = 0.78, R2ex = 0.77, and CCCex = 0.87. In addition, we have used QSAR-based virtual screening found 12 FDA compounds as in-silico hits, some of which could be used in clinical settings as ALK-TK inhibitors with a docking score ranging from -7.10 to -10.57 kcal/mol. For both wild-type and mutant ALK-TK, QSAR-based virtual screening predicted a PIC50 of 9.18 M for the new compound ZINC000150338819 with a docking score of -10.57 kcal/mol (RMSD 1.54Å). MD simulation and MMGBSA investigations confirm that the ZINC000150338819-ALK TK complex is stable for 200 ns for both wild-type and mutant ALK TK. To confirm the in-silico findings, MTT assay reveals that the Ledipasvir showed more inhibition as compared to ceritinib. This study suggests that the hit compound ZINC000150338819 may be a repurposed ALK TK inhibitor in drug discovery.