Structure Based Virtual Screening of Selected Phytochemicals aganist C1156y Mutant Anaplastic Lymphoma Kinase (ALK) using Molecular Docking and Admet Prediction

Author(s): Kanaka Durga Devi N*, Bharghava Bhushan Rao P, Ramya B, Sireesha U, Chandana M, Bhavana K, Likitha N, Harisitha P and Ravi Sankar K


Lung cancer is one of the fatal malignancies in both men and women worldwide. Anaplastic Lymphoma Kinase (ALK) rearrangements triggered the fusion of echinoderm microtubule-associated protein-like 4 (EML4) and ALK increasing the tyrosine kinase activity leading to cell proliferation and tumourigenesis causing Non-Small Cell Lung Cancer (NSCLC). Crizotinib emerged as a first-generation ALK inhibitor; however it developed resistance within a year of initiation of treatment in a few patients with deteriorating therapeutic outcomes. Various secondary mutations in ALK are responsible for crizotinib resistance in patients. C1156Y is a point mutation seen in patients resistant to crizotinib. Although second and third-generation ALK inhibitors are currently available, there is still a need to develop new ALK inhibitors as the existing compounds are developing resistance. In this study, we screened 940 phytochemicals against C1156Y mutant ALK to identify binding affinities. The results showed that three steroidal alkaloids Conessine, Solanocapsine, and Muldamine exhibited binding affinity (-9.0 kcal/mol) and are predicted to show activity in CNS for the prevention and management of CNS metastasis. We conclude that these 3 steroidal alkaloids are worth further in vitro and in vivo studies to emerge as potent C1156Y mutant ALK inhibitors.

image 10.4303/jdar/236156

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