In Vitro Anti-cancer Potential of Simarouba glauca Phytochemical Constituents against Breast Cancer: Using Molecular Docking and Simulation Approach

Abstract

Breast cancer is the second most prevalent malignancy and the leading cause of cancer-related mortality among women worldwide, highlighting the need for novel therapeutic agents. Natural products, particularly plant-derived phytochemicals, are promising candidates for anticancer drug discovery. This study employed an integrated in silico and in vitro approach to evaluate the anticancer potential of Simarouba glauca phytoconstituents targeting estrogen receptor alpha (ERα-3ERT), progesterone receptor (PR-1SQN), and HER2/neu (3PP0). Molecular docking using the Glide module of Schrödinger Maestro assessed binding affinities and interactions, followed by molecular dynamics simulations for stability analysis. Drug-likeness and pharmacokinetic properties were predicted using QikProp.Docking results identified PR as the most favorable target, with glaucarbolone, amarolide, and ailanthone demonstrating strong binding affinities (−12.095, −10.868, and −10.868 kcal/mol, respectively) and the interaction throughpolar residues such as ASN719, LEU718, THR894 and GLN725 were observed. In contrast, moderate binding affinities were observed against ERα, with glaucarubinone through THR347 and LEU536 and dehydroglaucarubinone toward HER2/neu (−6.017 kcal/mol) via interactions with SER728, THR862, and ASP863. Molecular dynamics simulations confirmed the structural stability of the top-ranked glaucarbolone–PR complex, supporting its favorable binding mode. ADMET analysis revealed that all evaluated quassinoids complied with Lipinski’s rule of five, and three exhibited favorable pharmacokinetic profiles. In vitro anti-proliferative studies demonstrated that Simarouba glauca leaf extract exhibits stronger activity against hormone-dependent breast cancer cells (MCF-7) compared to triple-negative cells (MDA-MB-231), with lower IC₅₀ values (61.56 and 155.06 µg/mL, respectively). These findings highlight the potential of Simarouba glauca phytochemicals, particularly PR-targeting phytochemical compounds, as promising lead candidates for breast cancer therapy and underscore the effectiveness of integrated in silico approaches in early-stage anticancer drug discovery.