Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries
Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries
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DOI：
10.1016/j.bmc.2009.05.070
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发表时间：
2009-07-15
影响因子：
3.5
通讯作者：
Hodder, Peter
中科院分区：
文献类型：
--
作者：
Minond, Dmitriy;Saldanha, S. Adrian;Hodder, Peter
Vim-2是一种Ambler B类金属β-内酰胺酶（MBL），能够水解广谱β-内酰胺抗生素。虽然MBL抑制剂的发现和开发仍然是一个活跃的研究领域，但一系列有效的小分子抑制剂尚未完全表征Vim-2。在所提出的研究中，化合物库筛选方法被用于从具有生物活性的化合物库以及集中的“点击”化学库中鉴定和表征Vim-2抑制剂。通过动力学研究表征由Vim-2筛选产生的四种最有效的Vim-2抑制剂，以确定Ki和酶抑制机制。结果，发现两种先前描述的药物，米托蒽醌（1，4-二羟基-5，8-双（[2-（[2-羟乙基]氨基）乙基]氨基）-9，10-蒽二酮）和4-氯汞苯甲酸（pCMB）具有活性，前者为非竞争性抑制剂（Ki = Ki ′ = 1.5 +/-0.2 μ M），后者为缓慢可逆或不可逆的抑制剂。此外，来自点击文库的两种新型磺酰基-三唑类似物被鉴定为有效的竞争性Vim-2抑制剂：不，不（（4-（（丁-3-炔基氧基）甲基）-1H-1，2，3-三唑-5-基）甲基）-4-碘苯磺酰胺（1，Ki = 0.41 +/- 0.03 μ M）和4-碘-N-（（4-（甲氧基甲基）-1H-1，2，3-三唑-5-基）甲基）苯磺酰胺（2，Ki = 1.4 +/- 0.10 μ M）。米托蒽醌和pCMB也被发现，加强亚胺培南的MIC和协同试验，采用大肠杆菌的功效。总之，所有四种化合物都代表了有用的化学探针，可用于在基于生物化学和微生物学的测定中进一步研究Vim-2抑制机制。(C)2009爱思唯尔有限公司保留所有权利。
VIM-2 is an Ambler class B metallo-beta-lactamase (MBL) capable of hydrolyzing a broad-spectrum of beta-lactam antibiotics. Although the discovery and development of MBL inhibitors continue to be an area of active research, an array of potent, small molecule inhibitors is yet to be fully characterized for VIM-2. In the presented research, a compound library screening approach was used to identify and characterize VIM-2 inhibitors from a library of pharmacologically active compounds as well as a focused 'click' chemistry library. The four most potent VIM-2 inhibitors resulting from a VIM-2 screen were characterized by kinetic studies in order to determine K-i and mechanism of enzyme inhibition. As a result, two previously described pharma cologic agents, mitoxantrone (1,4-dihydroxy-5,8-bis([2-([2-hydroxyethyl]amino)ethyl]amino)-9,10-anthracenedione) and 4-chloromercuribenzoic acid (pCMB) were found to be active, the former as a non-competitive inhibitor (K-i = K-i' = 1.5 +/- 0.2 mu M) and the latter as a slowly reversible or irreversible inhibitor. Additionally, two novel sulfonyl-triazole analogs from the click library were identified as potent, competitive VIM-2 inhibitors: N-((4-((but-3-ynyloxy)methyl)-1H-1,2,3-triazol-5-yl)methyl)-4-iodobenzenesulfonamide (1, K-i = 0.41 +/- 0.03 mu M) and 4-iodo-N-((4-(methoxymethyl)-1H-1,2,3-triazol-5-yl)methyl)benzenesulfonamide (2, K-i = 1.4 +/- 0.10 mu M). Mitoxantrone and pCMB were also found to potentiate imipenem efficacy in MIC and synergy assays employing Escherichia coli. Taken together, all four compounds represent useful chemical probes to further investigate mechanisms of VIM-2 inhibition in biochemical and microbiology-based assays. (C) 2009 Elsevier Ltd. All rights reserved.