Phytochemicals as potential AXL inhibitors for cancer therapy: A computational study.

The TAM (Tyro3, AXL, and Mer) receptor tyrosine kinases play vital roles in immunity and various complex diseases, particularly cancer. In this family, AXL has stood out as a promising target for therapeutic development due to its significant role in cancer progression and resistance to therapies. AXL and its ligand GAS6 promote metastasis and therapeutic resistance in several human cancers. Dysregulated AXL signaling is implicated in a spectrum of diseases, notably metastatic cancer. Elevated AXL expression correlates with drug resistance and poor survival in multiple cancers such as lung, breast, pancreatic, ovarian, colon, and melanoma. In this study, we conducted a virtual screening of phytochemicals sourced from the IMPPAT 2.0 database of Indian medicinal plants to identify potential AXL inhibitors. Preliminary screening was performed based on the physicochemical properties of the phytochemicals, followed by their interaction studies in molecular docking with AXL. Of 17,908 phytochemicals initially screened, 11,676 drug-like compounds complied with Lipinski's rule-of-five and were subjected to molecular docking and downstream analyses. Subsequent evaluation included ADMET analysis, PAINS examination, and PASS analysis to identify potent hits against AXL. From this screening, Neogitogenin and Solaspigenin emerged as promising candidates demonstrating favorable drug-like properties and significant binding potential with the AXL binding pocket. Neogitogenin and Solaspigenin showed binding affinities of -10.1 to -10.8 kcal/mol, favorable ADMET profiles, and with RMSD values ranging between 0.32 and 0.38 nm, indicating stable binding. Furthermore, molecular dynamics simulation over 200 ns revealed stable protein-ligand complexes with some minor conformational fluctuations. This study suggests that, after further experimentation, modulating AXL with natural compounds holds promise for combating human malignancies, potentially overcoming limitations of existing synthetic inhibitors such as R428.