PAINS in the assay: chemical mechanisms of assay interference and promiscuous enzymatic inhibition observed during a sulfhydryl-scavenging HTS.
PAINS in the assay: chemical mechanisms of assay interference and promiscuous enzymatic inhibition observed during a sulfhydryl-scavenging HTS.
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DOI：
10.1021/jm5019093
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发表时间：
2015-03-12
影响因子：
7.3
通讯作者：
Walters MA
中科院分区：
文献类型：
--
作者：
Dahlin JL;Nissink JW;Strasser JM;Francis S;Higgins L;Zhou H;Zhang Z;Walters MA
早期药物发现中的大量资源在不知不觉中被花费在人工制品和混杂的生物活性化合物上，而对这些不良行为的化学基础的了解往往没有在追求先导化合物的过程中进行探索。我们最近针对组蛋白乙酰转移酶Rtt109的硫基清除高通量筛选(HTS)中的几乎所有命中都是这样的化合物。在此，我们表征了本HTS确定的几种主要化学类型的分析干扰和混杂酶抑制的化学基础，包括一些泛分析干扰化合物(疼痛)。蛋白质质谱仪和报警核磁共振证实了这些化合物与半胱氨酸在多个蛋白质上发生共价反应。不幸的是，含有这些化学类型的化合物已被作为筛选活性物质发表在知名期刊上，甚至被吹捧为化学探针或临床前候选化合物。我们对这种硫醇反应性化学类型的详细表征和鉴定应该会加快有害化合物的分类，指导筛选文库设计，并防止对不受欢迎的化学物质的后续研究。
Significant resources in early drug discovery are spent unknowingly pursuing artifacts and promiscuous bioactive compounds, while understanding the chemical basis for these adverse behaviors often goes unexplored in pursuit of lead compounds. Nearly all the hits from our recent sulfhydryl-scavenging high-throughput screen (HTS) targeting the histone acetyltransferase Rtt109 were such compounds. Herein, we characterize the chemical basis for assay interference and promiscuous enzymatic inhibition for several prominent chemotypes identified by this HTS, including some pan-assay interference compounds (PAINS). Protein mass spectrometry and ALARM NMR confirmed these compounds react covalently with cysteines on multiple proteins. Unfortunately, compounds containing these chemotypes have been published as screening actives in reputable journals and even touted as chemical probes or preclinical candidates. Our detailed characterization and identification of such thiol-reactive chemotypes should accelerate triage of nuisance compounds, guide screening library design, and prevent follow-up on undesirable chemical matter.
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DOI：
10.2217/fon.14.51
发表时间：
2014-05
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Davids MS;Brown JR
通讯作者：
Brown JR
DOI：
10.1073/pnas.0912427107
发表时间：
2010-01-26
影响因子：
11.1
作者：
da Rosa, Jessica Lopes;Boyartchuk, Victor L.;Kaufman, Paul D.
通讯作者：
Kaufman, Paul D.
影响因子：
3.7
作者：
Dranchak P;MacArthur R;Guha R;Zuercher WJ;Drewry DH;Auld DS;Inglese J
通讯作者：
Inglese J
影响因子：
4.2
作者：
Dahlin JL;Walters MA
通讯作者：
Walters MA
影响因子：
1.1
作者：
Baell, Jonathan B.;Ferrins, Lori;Nikolakopoulos, George
通讯作者：
Nikolakopoulos, George