Affiliation:
1. Laboratorio de Biotecnología Farmacéutica Centro de Biotecnología Genómica Instituto Politécnico Nacional 88710 Reynosa México
2. Departamento de Bioquímica Instituto Nacional de Cardiología Ignacio Chávez 14080 Mexico City Mexico
3. Department of Pharmacy and Biotechnology Alma Mater Studiorum-University of Bologna Via Belmeloro 6 I-40126 Bologna Italy
Abstract
AbstractPhenothiazine derivatives can unselectively inhibit the trypanothione‐dependent antioxidant system enzyme trypanothione reductase (TR). A virtual screening of 2163 phenothiazine derivatives from the ZINC15 and PubChem databases docked on the active site of T. cruzi TR showed that 285 compounds have higher affinity than the natural ligand trypanothione disulfide. 244 compounds showed higher affinity toward the parasite's enzyme than to its human homolog glutathione reductase. Protein‐ligand interaction profiling predicted that the main interactions for the top scored compounds were with residues important for trypanothione disulfide binding: Phe396, Pro398, Leu399, His461, Glu466, and Glu467, particularly His461, which participates in catalysis. Two compounds with the desired profiles, ZINC1033681 (Zn_C687) and ZINC10213096 (Zn_C216), decreased parasite growth by 20 % and 50 %, respectively. They behaved as mixed‐type inhibitors of recombinant TR, with Ki values of 59 and 47 μM, respectively. This study provides a further understanding of the potential of phenothiazine derivatives as TR inhibitors.
Subject
Organic Chemistry,Computer Science Applications,Drug Discovery,Molecular Medicine,Structural Biology