Identification of Adenosine Deaminase Inhibitors by Metal-binding Pharmacophore Screening.
Identification of Adenosine Deaminase Inhibitors by Metal-binding Pharmacophore Screening.
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DOI：
10.1002/cmdc.202000271
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发表时间：
2020-11-18
期刊：
影响因子：
3.4
通讯作者：
Cohen SM
中科院分区：
文献类型：
--
作者：
Adamek RN;Ludford P;Duggan SM;Tor Y;Cohen SM
腺苷脱氨酶(ADA)是一种人单核锌金属酶，能将腺苷转化为肌苷。ADA是一种有效的癌症药物靶点，但最近几乎没有针对这种酶的新疗法的开发工作。缺乏新的进展可以部分归因于缺乏合适的检测方法用于ADA的高通量筛选(HTS)。为了更快地发现这一靶点的药物，开发了一种体外检测方法，该方法利用ADA将可见发射的腺苷类似物转化为相应的荧光肌苷类似物，这可以通过荧光强度的变化进行监测。利用这一方法，以HTS形式筛选了含有金属结合药效团(MBP)的~350个小分子文库，以鉴定新的ADA抑制剂支架。这种方法得到了一种新的金属结合支架，其KI值为26±1μM。通过高通量筛选发现了金属酶腺苷脱氨酶的金属结合抑制剂。一种结合活性支架的片段合并策略导致了咪唑啉类抑制剂的发现。这项工作证明了金属结合抑制剂为治疗干预提供ADA抑制的新途径的潜力。
Adenosine deaminase (ADA) is a human mononuclear Zn2+ metalloenzyme that converts adenosine to inosine. ADA is a validated drug target for cancer, but there has been little recent work on the development of new therapeutics against this enzyme. The lack of new advancements can be partially attributed to an absence of suitable assays for high-throughput screening (HTS) against ADA. To facilitate more rapid drug discovery efforts for this target, an in vitro assay was developed that utilizes the enzymatic conversion of a visibly emitting adenosine analogue to the corresponding fluorescent inosine analogue by ADA, which can be monitored via fluorescence intensity changes. Utilizing this assay, a library of ~350 small molecules containing metal-binding pharmacophores (MBPs) was screened in an HTS format to identify new inhibitor scaffolds against ADA. This approach yielded a new metal-binding scaffold with a Ki value of 26±1 μM. Metal-binding inhibitors of the metalloenzyme adenosine deaminase (ADA) were discovered by high-throughput screening. A fragment merge strategy of combining active scaffolds led to the discovery of an imidazoline-based inhibitor. This work demonstrates the potential of metal-binding inhibitors to provide novel routes for ADA inhibition for therapeutic intervention.
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影响因子：
7.3
作者：
Chen AY;Thomas PW;Stewart AC;Bergstrom A;Cheng Z;Miller C;Bethel CR;Marshall SH;Credille CV;Riley CL;Page RC;Bonomo RA;Crowder MW;Tierney DL;Fast W;Cohen SM
通讯作者：
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