Modulation of ABCB1 by Erinacerin S: Binding dynamics and transmembrane helix remodeling

Erinacerins are a group of bioactive heterocyclic organic compounds known as Isoindolin-1-one metabolites with the molecular formula C₈H₉N, derived from the mycelia or fruiting bodies of the mushroom Hericium erinaceus. They are known for their neuroprotective, anti-inflammatory, and anticancer properties. Erinacerins inhibit the growth of breast, colon, and lung cancer cells; induce apoptosis, prevent angiogenesis, and overcome cancer therapy. Some Erinacerins lack a documented therapeutic target or a mechanism of action. This study aimed to identify therapeutic protein targets for Erinacerins that have been verified to exhibit cytotoxic effects in cancer cell lines. A virtual metabolite screening of Hericium erinaceus was conducted using the MeFSAT database. Following a systematic two-step filtering process, erinacerins meeting an established criterion were selected. A target search was performed based on Erinacerin's structure, leading to the identification of the receptor Multidrug Resistance Protein (MDR)1 or P-glycoprotein (P-gp, ABCB1) as a potential target for Erinacerin S. Results showed a strong binding affinity to the ABCB1 canonical drug-binding pocket, consistently interacting with transmembrane domains (TMs) 7, 9, and 12. Van der Waals forces dominated binding energetics, with PHE343, MET986, and LEU225 as key stabilizing residues. TM9 emerged as a critical pharmacophore region. Structural analyses revealed conformational plasticity in the TM4 and TM6 helices, suggesting an allosteric mechanism. RMSD and Rgyr variations across replicas indicated dynamic ligand-receptor interactions, supporting the potential for bidirectional modulation. This study provides the first evidence supporting Erinacerin S as a potential ABCB1 inhibitor, suggesting its role in overcoming multidrug resistance in cancer therapy.