title: Identification of M. tuberculosis thioredoxin reductase inhibitors based on high-throughput docking using constraints.
abstract: A virtual screening campaign is presented that led to small molecule inhibitors of thioredoxin reductase of Mycobacterium tuberculosis (MtTrxR) that target the protein-protein interaction site for the substrate thioredoxin (Trx). MtTrxR is a promising drug target because it dominates the Trx-dependent hydroperoxide metabolism and the reduction of ribonucleotides, thus facilitating survival and proliferation of M. tuberculosis. Moreover, MtTrxR sufficiently differs from its human homologs to suggest the possibility of selective inhibition if the MtTrxR-Trx interaction site is targeted. To this end, high-throughput docking of 6.5 million virtual compounds to the thioredoxin binding site of MtTrxR combined with constraints as filtering steps was applied. A total of 170 high-scoring compounds yielded 18 compounds that inhibited MtTrxR with IC50 values up to the low micromolar range, thus revealing that the protein-protein interaction site of MtTrxR is indeed druggable. Most importantly, selectivity toward MtTrxR in comparison to human TrxR (HsTrxR) is also demonstrated.
authors.affiliation: MSD Animal Health Innovation GmbH, Schwabenheim, Germany. oliver.koch@tu-dortmund.de
authors.forename: Oliver
authors.initials: O
authors.lastname: Koch
authors.forename: Timo
authors.initials: T
authors.lastname: Jäger
authors.forename: Kristin
authors.initials: K
authors.lastname: Heller
authors.forename: Purushothama Chary
authors.initials: PC
authors.lastname: Khandavalli
authors.forename: Jette
authors.initials: J
authors.lastname: Pretzel
authors.forename: Katja
authors.initials: K
authors.lastname: Becker
authors.forename: Leopold
authors.initials: L
authors.lastname: Flohé
authors.forename: Paul M
authors.initials: PM
authors.lastname: Selzer
mesh_terms: D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D057166:High-Throughput Screening Assays; D006801:Humans; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013880:Thioredoxin-Disulfide Reductase