Implementation of pharmacophore-based 3D QSAR model and scaffold analysis in order to excavate pristine ALK inhibitors

Keypoints A total of 1574 plant-derived compounds was explored for their ALK inhibitory activity. Possible mechanistic action of the hits was proposed. Pearson's correlation coefficient was used to examine the statistical significance of the computational analysis. The utilisation of anaplastic lymphoma kinase (ALK) inhibitors has unveiled a magnificent clinical activity in ALK-positive non-small cell lung cancer (NSCLC), as well as against the sanctuary site of CNS in selected patients. However, the unsatisfactory survival rates along with unaccomplished overall cure for NSCLC (specifically in metastatic diseases), create an importunity for superior and perpetuating research for the establishment of novel ALK inhibitors in order to ameliorate the consequences of NSCLC. Intriguingly, a few plant-based drugs have paved their way to phase II clinical trial, inspired by which, the present study essayed to unearth novel ALK inhibitors from the NPACT database which comprises 1574 plant-derived compounds that exhibit anti-cancerous activity, using 3D QSAR model (AAADD.1882). Furthermore, multiple docking algorithms (PL-PatchSurfer2 and Glide) were employed to eliminate the false positive prediction. In essence, the strength of the association between the IC50 values and docking score was measured by Pearson's correlation coefficient (r). Altogether, our anatomisation yielded three hits, namely; obovaten (NPACT00821), pinoresinol (NPCT00008) and (3S)-3 ',7-dihydroxy-2 ',4 ',5 ',8-tetramethoxyisoflavan (NPACT00018) with higher docking scores, predicted anti-cancer and pharmaceutically appurtenant properties with greater CNS involvement. Ultimately, molecular dynamic (MD) simulation highlights the real time evidence for stability of these hit compounds. It is noteworthy to mention that all the hits constitute of particular scaffolds which play a major role in the downregulation of some ALK-positive lung cancer pathways. We speculate that the outcomes of this research are of substantial prominence in the rational designing of novel and efficacious ALK inhibitors.