A Bioinorganic Approach to Fragment-Based Drug Discovery Targeting Metalloenzymes.
A Bioinorganic Approach to Fragment-Based Drug Discovery Targeting Metalloenzymes.
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DOI：
10.1021/acs.accounts.7b00242
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发表时间：
2017-08-15
影响因子：
18.3
通讯作者：
Cohen SM
中科院分区：
文献类型：
--
作者：
Cohen SM
金属依赖型酶（即金属酶）在所有酶中占很大比例，在包括DNA修饰、蛋白质内稳态、抗生素抗性等众多生物过程中至关重要。因此，金属酶为药物研发提供了一个广阔且大多尚未开发的空间。发现针对金属酶的有效治疗药物正处于生物无机化学和药物化学的交叉领域，需要这两个领域的专业知识、方法和策略来开展有效的研究。在这篇综述中，我们描述了将生物无机化学的原理和方法与药物化学的原理和方法相结合，以弥合这些领域之间的差距并针对一类重要的药物靶点进行研究的努力。
基于片段的药物发现（FBDD）是一种重要的药物发现方法，特别适合用于金属酶抑制剂的研发。FBDD使用相对较小但针对性很强的化学结构，从而能够构建针对目标酶特定特征的优势分子集合。对于金属酶抑制而言，这个特定特征相当明显，即金属依赖型活性位点。令人惊讶的是，在我们开展工作之前，针对金属酶金属活性位点结合的多种分子片段的探索在很大程度上是未被开发的。通过构建一个适度的金属结合药效团（MBP）库，我们已经能够为许多金属酶找到先导化合物，并且从这些先导化合物中开发出通过新作用机制起作用的抑制剂。重点介绍了一个使用该策略来确定锌依赖型Rpn11（蛋白酶体的一个组分）的首创抑制剂的具体案例研究。
FBDD在金属酶抑制剂研发中的应用引发了其他几个引人关注的问题，例如金属酶活性位点如何影响这些结合片段的配位化学，如何为给定的金属酶确定最佳片段等等。在金属酶抑制方面，最重要且令人担忧的问题围绕特异性问题展开，即金属酶抑制剂是否能像其他小分子抑制剂（即抑制活性位点不利用金属的酶的化合物）一样具有选择性和特异性。这也引出了金属酶抑制剂是否可能更广泛地干扰金属组的问题。讨论了为解决这些及相关问题所做的努力，期望我们的研究结果能够回答其中一些问题，缓解一些担忧，并激发人们对这一重要但被低估的药物靶点类别产生更大的兴趣。
Metal-dependent enzymes (i.e. metalloenzymes) make up a large fraction of all enzymes and are critically important in a wide range of biological processes, including DNA modification, protein homeostasis, antibiotic resistance, and many others. Consequently, metalloenzymes represent a vast, and largely untapped space for drug development. The discovery of effective therapeutics that target metalloenzymes lies squarely at the interface of bioinorganic and medicinal chemistry and requires expertise, methods, and strategies from both fields to mount an effective campaign. In this Account, our effort to bring together the principles and methods of bioinorganic with those of medicinal chemistry to bridge the gap between these fields and address an important class of medicinal targets are described. Fragment-based drug discovery (FBDD) is an important drug discovery approach that is particularly well suited for metalloenzyme inhibitor development. FBDD uses relatively small, but highly targeted chemical structures that allow for the assembly of privileged molecular collections that focus on a specific feature of the target enzyme. For metalloenzyme inhibition the specific feature is rather obvious, namely a metal-dependent active site. Surprisingly, prior to our work the exploration of diverse molecular fragments for binding the metal active sites of metalloenzymes was largely unexplored. By assembling a modest library of metal-binding pharmacophores (MBPs), we have been able to find lead hits for many metalloenzymes, and from these hits develop inhibitors that act via novel mechanisms of action. A specific case study on the use of this strategy to identify a first-in-class inhibitor of zinc-dependent Rpn11 (a component of the proteasome) is highlighted. The application of FBDD for the development of metalloenzyme inhibitors has raised several other compelling questions, such as how the metalloenzyme active site influences the coordination chemistry of these bound fragments, and how one can identify the best fragments for a given metalloenzyme, and many others. Among the most significant, and concerning, questions for metalloenzyme inhibition reside around the question of specificity and whether metalloenzyme inhibitors can be as selective and specific as other small molecule inhibitors (i.e., compounds that inhibit enzymes that do not utilize a metal at their active site). This also leads to the question of whether metalloenzyme inhibitors might interfere more broadly with the metallome. Efforts to address these and related questions are discussed, with the expectation that our findings will answer some of these questions, alleviate some of these concerns, and encourage greater interest in this important, undervalued class of drug targets.
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影响因子：
4
作者：
Bauman, Joseph D.;Patel, Disha;Baker, Steven F.;Vijayan, R. S. K.;Xiang, Amy;Parhi, Ajit K.;Martinez-Sobrido, Luis;LaVoie, Edmond J.;Das, Kalyan;Arnold, Eddy
通讯作者：
Arnold, Eddy
DOI：
10.1039/c3cc41191e
发表时间：
2013-04-21
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Fullagar JL;Garner AL;Struss AK;Day JA;Martin DP;Yu J;Cai X;Janda KD;Cohen SM
通讯作者：
Cohen SM
影响因子：
4.6
作者：
Puerta, DT;Cohen, SM
通讯作者：
Cohen, SM
影响因子：
3.4
作者：
Agrawal, Arpita;Johnson, Sherida L.;Jacobsen, Jennifer A.;Miller, Melissa T.;Chen, Li-Hsing;Pellecchia, Maurizio;Cohen, Seth M.
通讯作者：
Cohen, Seth M.
影响因子：
7.3
作者：
Martin DP;Blachly PG;McCammon JA;Cohen SM
通讯作者：
Cohen SM