Abstract
In addition to several other malignancies, the ligand-activated aryl hydrocarbon receptor (AhR) signaling pathway has been found to enhance the risk of triple-negative breast cancer (TNBC). Many natural compounds of pharmaceutical importance are identified as antagonistic exogenous ligands of AhR. The expressional lack of hormone receptors coupled with adverse prognosis leads to the absence of molecular-targeted therapy in TNBC. Hence, discovering low-cost therapeutic alternatives involving the identification of effective biomarkers is an urgent necessity. This study investigates the binding mechanism of resveratrol, a dietary exogenous AhR ligand against the high-penetrance genes in TNBC, viz., PALB2, TP53, PTEN, STK11, BRCA1, and BRCA2. Post-pharmacokinetic evaluation, molecular docking revealed the binding energy scores of resveratrol against the six TNBC high-penetrance receptors. The results obtained from docking were confirmed by molecular dynamics simulation including principal component analysis, calculation of total interaction energy, and free-energy landscape computation. PALB2 emerged as a promising therapeutic receptor of resveratrol. Furthermore, the PALB2-resveratrol binding dynamics were evaluated against olaparib, an FDA-approved standardized TNBC inhibitor. Our study reveals comparatively better chemistry of PALB2-resveratrol than PALB2-olaparib. Considering the current surge in the discovery of precision medicine in biomarker-based cancer therapeutics, this study proposes PALB2-resveratrol as a unique drug-receptor combination thus awaiting validation through in vitro studies.