Investigation of phytoconstituents interactions with human Src kinase in a bid to improve cholangiocarcinoma chemotherapy: An in-silico approach.

Cholangiocarcinoma (CCA), a malignancy of the biliary epithelium, remains a formidable clinical challenge due to its aggressive nature, late-stage diagnosis, and resistance to chemotherapy. There is an urgent need to identify potent drugs. Medicinal plants are considered a rich source of therapeutic agents since prehistoric times, also mentioned in Ayurveda. This study aims to investigate the interactions of phytoconstituents from medicinal plants native to the North-western Himalayan regions with the Src protein PDB ID: 4MXO to improve cholangiocarcinoma by in silico approach. Molecular docking was performed by using the AutoDock Vina tool. Toxicity and drug-likeness were predicted using online servers (Protox3.0 and SwissADME. Protein-ligand stability was studied through molecular dynamics simulation for 500 ns by using GROMACS software. Molecular docking study showed that among all the selected 109 phytoconstituents, eriodictyol-7-glucuronide, apigenin, thalirugine, clicoemodin, apigenin-7-o-glucuronide, beta-sitosterol-beta-D-glucoside, rutin, 8-oxyberberine, berberine, thalirugidine, apigenin-7-o-glucoside, stigmasterol, 8-prenylnaringenin, thalicarpine, and sesamin showed the best interaction with the target protein. Toxicity and drug likeness data suggested that Apigenin & apigenin-7-o-glucoside are safer drug-like compounds, also have similar binding energy and interactions with amino acids to standard inhibitor bosutinib, and apigenin is selected for further molecular dynamic simulation because it is more economical than apigenin-7-o-glucoside. MD simulation data suggested that apigenin and apigenin-7-o-glucoside in complex with target protein 4MXO have stable RMSD & radius gyration for a 500 ns period. This study suggested that among all the selected phytoconstituents selected 109 phytoconstituents, apigenin has a potential drug molecule which can be further evaluated by in vitro and in vivo for cholangiocarcinoma (CCA).