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首页> 外文期刊>Journal of Medicinal Chemistry >Identification of M. tuberculosis thioredoxin reductase inhibitors based on high-throughput docking using constraints
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Identification of M. tuberculosis thioredoxin reductase inhibitors based on high-throughput docking using constraints

机译：基于约束条件的高通量对接鉴定结核分枝杆菌硫氧还蛋白还原酶抑制剂

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摘要

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 IC_(50) 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.
机译：提出了一个虚拟筛选活动，该活动导致结核分枝杆菌（MtTrxR）的硫氧还蛋白还原酶小分子抑制剂靶向基质硫氧还蛋白（Trx）的蛋白质-蛋白质相互作用位点。 MtTrxR是有前途的药物靶标，因为它支配Trx依赖的氢过氧化物代谢和核糖核苷酸的减少，从而促进结核分枝杆菌的生存和增殖。此外，MtTrxR与它的人类同源物充分不同，表明如果靶向MtTrxR-Trx相互作用位点，则有选择性抑制的可能性。为此，应用了650万种虚拟化合物的高通量对接至MtTrxR的硫氧还蛋白结合位点，并结合了过滤步骤的约束条件。总共170种高得分化合物产生了18种抑制MtTrxR的化合物，其IC_（50）值高达低微摩尔范围，因此表明MtTrxR的蛋白质-蛋白质相互作用位点确实是可药物治疗的。最重要的是，还证明了与人类TrxR（HsTrxR）相比，对MtTrxR的选择性。

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