Identification of a Novel Trifluoromethyl-Bearing Flavonoid as a Promising Androgen Receptor Antagonist: Structure-Based Virtual Screening and In Vitro Study.

Aberrant androgen receptor (AR) expression is the primary driver of prostate cancer progression. While androgen deprivation therapy and AR antagonists are the cornerstones of AR-signaling suppression, their long-term efficacy is frequently compromised by adverse effects and the emergence of drug resistance. Consequently, there is an urgent need to identify novel therapeutic agents. In this study, we screened a library of 112 nonsteroidal compounds (flavonoids and chalcones derivatives) using an integrative in silico and in vitro approach. Initial molecular docking revealed that compounds , , and possessed markedly favorable docking scores than the clinical reference, enzalutamide. Subsequent 300-ns molecular dynamics simulations supported the structural stability of these complexes and identified critical interacting residues, including L704, G708, M742, M745, V746, M749, F764, L873, and T877. Notably, in vitro assays demonstrated that compound , a flavone derivative bearing a trifluoromethyl group, substantially suppressed the proliferation of androgen-dependent (LNCaP) cells. Furthermore, treatment effectively down-regulated the expression of both the AR and its primary downstream transcriptional target, prostate-specific antigen. Collectively, these findings highlight compound as a promising lead scaffold for the development of targeted AR therapies for prostate cancer management.