Pharmacophore Modeling for Pleurotin Derivatives Targeting Human Thioredoxin Reductase

Abstract

Pleurotin is a natural compound and potent inhibitor of thioredoxin reductase (TrxR) enzyme, which is a target for cancer chemotherapy. The present study proposes a pharmacophore model for TrxR inhibitors based on the in silico analysis of 34 pleurotin analogues. The results led to ligand 33 with a flexible -SR side-chain at p-quinone and a H-bond donor -CH2NH2 at the oxepane ring. The ligand-TrxR binding free energy was -236 kJ mol-1 for 33, better than pleurotin (-166 kJ mol-1 ). The results provide a clear and practical guide to design pleurotin derivatives with anticancer potential that could expand the pharmacological potential of this class of natural products.