EVALUATION OF PHYTOCHEMICALS FROM TINOSPORA CORDIFOLIA AGAINST ONCOGENIC AND RESISTANCE-ASSOCIATED TARGETS IN LOW-GRADE SEROUS OVARIAN CARCINOMA

Abstract

Low-grade serous ovarian carcinoma (LGSC) is not frequent but chemo-resistant subtype of epithelial ovarian cancer. Key features of this particular subtype are slow proliferation and poor response to conventional chemotherapy treatment. This study aims to identify plant-derived compounds that are capable of modulating key target involved in oncogenic and resistance pathways in LGSC. Here, the focus was on six molecular targets KRAS, BRAF, MEK1 are the oncogenic drivers of LGSC whereas as HES1, EGFR, PIK3CA are involved in drug-resistance. Phytochemicals from Tinospora cordifolia (Giloy) which is a traditional medicinal plant belonging to the Menispermaceae family has been gaining significant attention recently due to its known anticancer properties. These phytocompounds were explored using a computational approach. Through literature mining a total of eighteen phytocompounds were shortlisted and seven with favourable ADME and drug-likeness profiles (DL score ≥ 0.5) were selected for further study. These shortlisted candidates were taken for molecular docking using AutoDock Vina using Pyrx, where Luteolin, Berberine, and Dehydrodiscretamine and Magnoflorine showed strong binding with key LGSC targets (>8.5 kcal/mol). All the promising ligand–protein complexes were then further analysed through molecular dynamics (MD) simulations using Desmond and Google Colab. Out of the tested protein-ligand complexes, good structural stability and a consisitent binding throughout the course of simulation was onserved in case of Luteoli-BRAF, Berbine-EGFR and Dehydrodiscretamine BRAF complexes. The PI3KCA-Berberine complex however showed moderate stability. MM/GBSA binding energy analysis further supported their binding affinity and complex stability. Overall, Luteolin, Berberine, and Dehydrodiscretamine emerged as the strongest multitarget inhibitors among all the tested phytochemicals. These compounds have potential to disrupt oncogenic signalling and overcome chemoresistance in LGSC. These findings provide a computational framework and lay the foundation for future experimental validation and therapeutic development using Tinospora cordifolia phytochemicals.