Journal article

Publication year: 2013

Pages: 4849-4859

Journal: Journal of Medicinal Chemistry

Volume number: 56

Issue number: 12

ISSN: 0022-2623

eISSN: 1520-4804

DOI Link: https://doi.org/10.1021/jm3015734

Publisher: American Chemical Society

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.

Harvard Citation style: Koch, O., Jäger, T., Heller, K., Khandavalli, P., Pretzel, J., Becker, K., et al. (2013) Identification of M. tuberculosis Thioredoxin Reductase Inhibitors Based on High-Throughput Docking Using Constraints, Journal of Medicinal Chemistry, 56(12), pp. 4849-4859. https://doi.org/10.1021/jm3015734

APA Citation style: Koch, O., Jäger, T., Heller, K., Khandavalli, P., Pretzel, J., Becker, K., Flohe, L., & Selzer, P. (2013). Identification of M. tuberculosis Thioredoxin Reductase Inhibitors Based on High-Throughput Docking Using Constraints. Journal of Medicinal Chemistry. 56(12), 4849-4859. https://doi.org/10.1021/jm3015734