Journal of Complementary and Alternative Medical Research

Background: Lung cancer is one of the most common and deadliest cancers worldwide, contributing significantly to cancer-related morbidity and mortality. Ongoing research in this field focuses on the development of effective preventive strategies, early screening methods, and improved therapeutic interventions to reduce mortality and enhance the quality of life of affected patients.

Methods: The present study aimed to investigate the potential effects of substituted benzylidene-3,4,5-trihydroxybenzohydrazide derivatives and 5-(substituted phenylamino) benzene-1,2,3-triol derivatives under lung cancer conditions. For this purpose, pre-ADMET, Molinspiration, molecular docking, and docking interaction studies were carried out to evaluate their pharmacokinetic properties and binding interactions with the target protein.

Results and Discussion: Computational investigations demonstrated that the designed substituted benzylidene-3,4,5-trihydroxybenzohydrazide derivatives and 5-(substituted phenylamino) benzene-1,2,3-triol derivatives possess favorable drug-likeness and predicted bioavailability characteristics. To further assess their inhibitory potential toward the tyrosine kinase protein target (PDB ID: 6CU6), a set of thirty newly designed derivatives was subjected to molecular docking analysis.

The docking performance of these compounds was evaluated in terms of MolDock score, hydrogen-bonding interactions, and steric contacts, and the results were benchmarked against the reference tyrosine kinase inhibitor Erlotinib. The standard ligand Erlotinib exhibited the highest binding affinity with a MolDock score of −155.409, forming key hydrogen bond interactions with residues Ser17, Gly15, Asn116, and Asp33. In addition, notable steric interactions were observed with Glu31, Val29, Gly15, Ser17, Asp13, and Asp33, indicating stable accommodation within the active binding pocket.

Among the screened derivatives, compound GA28 demonstrated comparatively strong binding affinity, with a MolDock score of −140.836. This ligand established an extensive hydrogen-bonding network involving Gly60, Lys16, Gly13, Val29, Asp33, Tyr32, Arg12, and Thr35, together with steric interactions involving  by Tyr32, Lys16, Ser17, Gly31, Ala18, and Gly15. Likewise, compound GA18 showed appreciable binding affinity, with a MolDock score of −128.656. It formed multiple hydrogen bonds with Arg12, Thr35, Lys16, Gly15, Val14, Ala11, Asp30, Val29, and Glu31, while steric contacts were mainly observed with Asp30, Arg12, Lys16, and Ser17.

Overall, the docking analysis indicates that GA28 and GA18 exhibit favorable interaction patterns and significant binding stability within the catalytic site of the tyrosine kinase target. These observations highlight their potential as promising lead scaffolds for further structural refinement and subsequent experimental validation.

Conclusion: These findings suggest that the designed compounds exhibit favorable interactions with the active site residues, indicating their potential as tyrosine kinase inhibitors.