In-silico approach to investigate the phytochemicals of Terminalia arjuna as multitarget inhibitors of proteins involved with lung cancer

Abstract

Background: Existing medications for treating cancer are reported to exhibit severe side effects, therefore, there is an urgent need to address these unprecedented health risks. With the advancements in ethnobotanical studies and researches on phytochemicals, information on several medicinal plants is being revisited nowadays. Terminalia arjuna is a widely used medicinal plant in ayurvedic and Unani medicine for curing several diseases. Although the bioactives from this plant are reported to possess anti-carcinogenic, antiproliferative and antioxidant activities, information on the potentials of its specific phytoconstituents on the inhibition of receptor molecules associated with lung cancer is scarce. Objectives: The primary goal of this study is to virtually screen the phytochemicals of Terminalia arjuna as potential drug candidate molecules for lung cancer. Considering all major reported receptor molecules that inevitably take part in lung cancer, it highlights the phytochemicals as novel multitargeted inhibitors of proteins responsible for lung cancer. Method: A thorough literature review was done to select twenty-seven receptor molecules associated with lung cancer cases. The molecular docking study using PyRx predicts protein-ligand interactions and identifies potential drug targets. Evaluating the ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of the phytochemicals present in Terminalia arjuna, this study takes into account of thirty-four bioactive compounds as the chosen ligands in molecular docking. The binding affinity, inhibition constant (Ki), and the interacting residues of these phytochemicals with the receptors are compared with the docking results of twelve selected standard anticancer drugs. The study finally categorizes the phytochemicals that can potentially act as multitargeted inhibitors of proteins associated with lung cancer. Results: The results from PyRx highlighted the phytoconstituents having a higher binding affinity with inhibition constant comparable to the standard drugs. Among the standard anticancer drugs, alectinib, pralsetinib, and ibrutinib are marked as potent inhibitors of several lung cancer receptors. The phytochemicals of Terminalia arjuna proved to be the potential candidates against ALK2, ALK5, DDR2, BRAF, KRAS, Tankyrase, vasopressin V2, VEGFR1 and VEGFR2 mediated lung cancer but the effectiveness (in comparison to the standard drugs) is limited against Bcl-2, IL22R1, NCAM, RET, MET and ROS1 receptors. Conclusions: The findings indicate that phytochemicals namely luteolin, friedelin, oleanolic acid, and 14,16-dianhydrogitoxigenin bind strongly to multiple receptors under consideration with high affinity and hence could be investigated as effective alternatives for treating lung cancer with minimal side effects.