Introduction: Recent years has witnessed major paradigm shifts in the treatment of NSCLC with the emergence of biomarkers and targeted therapies. Most importantly, ALK is a validated biomarker and its inhibition using targeted therapies have had significant effects on patients suffering from NSCLC. However, emergence of drug resistance has limited the usage of these agents in the patients. Objective: In the present objective, e-pharmacophore based virtual screening was employed to discover potent ALK inhibitors from a natural compound database, TIPdb. Result: Screening of TIPdb using the e-pharmacophore model (DDRRR) retrieved 1000 hits. The docking procedures and ADME analysis led to the identification of piperphilippinin VI as the best hit. Further interaction analysis showed that piperphilippinin VI exhibited crucial interactions with kinase domain of the protein, which is the major targeting site for ALK inhibitors. Note that, PASS prediction analysis highlighted the presence of anti-neoplastic activity of the hit molecule towards lung cancer in particular NSCLC. Conclusion: The comprehensive analysis of the present study shows that, piperphilippinin VI has higher binding affinity, low toxicity profiles and increased CNS activity. We believe that these observations are of immense importance in the rational designing of a novel and potent ALK inhibitors from natural sources. © 2018, Association of Pharmaceutical Teachers of India. All rights reserved.