Discovery of protein arginine methyltransferase 1 inhibitor by structure-based pharmacophore modeling, virtual screening, molecular dynamics simulations, and the enhancement of paclitaxel's antitumor activity

Abstract

Protein arginine methyltransferase 1 (PRMT1), a key epigenetic regulator, is implicated in tumor progression and therapy resistance. Here, we identify a novel PRMT1 inhibitor, YH-4, through structure-based pharmacophore modeling, virtual screening, and molecular dynamics simulations. YH-4 demonstrates potent PRMT1 inhibition (IC₅₀ = 4.11 μM) and dose-dependently suppresses asymmetric dimethylarginine (ADMA) levels and histone H4R3me2a modification in triple-negative breast cancer (TNBC) cells. In vitro, YH-4 induces cell cycle arrest, apoptosis, and inhibits migration and colony formation in MDA-MB-231 cells. Notably, YH-4 synergizes with paclitaxel (PTX), reducing cell viability and enhancing PTX efficacy in a xenograft model in vivo. This study is the first to confirm that PRMT1 inhibitors act as chemotherapeutic sensitizers for paclitaxel in the treatment of TNBC. Molecular dynamics simulations confirm stable binding of YH-4 to PRMT1, driven by hydrogen bonding and hydrophobic interactions. This study highlights YH-4 as a promising therapeutic agent to overcome paclitaxel resistance in TNBC and provides a computational-experimental framework for developing PRMT1-targeted therapies.

Keywords: Chemotherapeutic sensitizers; PRMT1 inhibitor; Triple-negative breast cancer; Virtual screening.