Pharmacophore-based designing of putative ROS-1 targeting agents for NSCLC.

ABSTRACT

Non-small cell lung cancer (NSCLC) is a fatal non-immunogenic malignancy, and proto-oncogene receptor tyrosine kinase (ROS-1) is one of its clinically relevant biomarkers. In this context, herein, we report a series of benzimidazol-2-amine derivatives which were synthesized on the basis of the pharmacophore of ROS-1 and evaluated for anti-proliferative activity. For this, the in silico receptor-ligand pharmacophore model of ROS-1, previously published by our own group, was utilized to screen out an in-house database of small molecule heterocycles. Docking analysis of the selected compounds was carried out within the active site of wild-type (WT) ROS-1 as well as Gly2032Arg mutant ROS-1 protein, which confirmed the retention of conserved interaction between selected molecules and hinge region amino acids Glu2027 and Met2029. Docking was followed by molecular dynamics simulations for the stability of the complexes and calculation of the MM-GBSA score for binding affinity. Finally, compounds were synthesized and the anti-proliferative potential of compounds was evaluated using the A549 cell line. Compounds 3a and 3b presented significant GI50 values between 23.0 and 25.4 µM, among all the tested compounds.