Screening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum.
Screening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum.
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DOI：
10.1186/1475-2875-13-190
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发表时间：
2014-05-27
期刊：
影响因子：
3
通讯作者：
Willis P
中科院分区：
文献类型：
--
作者：
Avery VM;Bashyam S;Burrows JN;Duffy S;Papadatos G;Puthukkuti S;Sambandan Y;Singh S;Spangenberg T;Waterson D;Willis P
鉴于需要不断向生产线提供适应于不同和更严格的目标产品特征的新的抗疟疾剂（例如，新的作用方式、阻断传播的活性或长期的化学保护作用），一个由250，000多种化合物组成的化学库已经在血液阶段恶性疟原虫生长抑制试验中进行了评估，并进一步评估了化学多样性和新奇。用于对来自化学文库的命中进行分类的选择级联从稳健的三步体外测定开始，然后对所得确认命中进行计算机模拟分析。在达到选择性和效价的预定义要求后，对命中集进行计算分析以评估化学性质和多样性。此外，已知的市售抗疟疾药物在由命中物定义的化学空间中作为“路标”共同聚集。然后，在cerebro中对化学结构进行评价，以确定目前是或曾经是抗疟疾药物化学计划重点的支架。接下来，根据宽松的物理化学参数进行优先级排序，沿着结构类似物的搜索。最终，进行具有所需性质的新型化学型的合成，随后在恶性疟原虫生长抑制测定中重新测试所得化合物。这一筛查活动导致1.25%的初次命中率，在确认性重复筛查后下降至0.77%。根据预定义的效价（EC50 < 1 μM）和选择性（SI > 10）标准，178种化合物进入了下一步，其中考虑了化学多样性，物理化学性质和新奇评估。这导致选择了15个不同的化学系列。应用选择级联来优先化从针对血液阶段恶性疟原虫的中等大小的化学文库的筛选产生的命中。重点放在化学新奇，计算聚类，已知的抗疟疾化学型的数据挖掘和宽松的物理化学过滤器的应用，是关键的过程。这导致选择了15个化学系列，其中10个在测试新合成的样品时证实了它们的活性。
In view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e.g., new modes of action, transmission-blocking activity or long-duration chemo-protection), a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty. The selection cascade used for the triaging of hits from the chemical library started with a robust three-step in vitro assay followed by an in silico analysis of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational analysis to assess chemical properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as ‘signposts’ in the chemical space defined by the hits. Then, in cerebro evaluation of the chemical structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chemistry programmes. Next, prioritization according to relaxed physicochemical parameters took place, along with the search for structural analogues. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compounds were subsequently retested in a P. falciparum growth inhibition assay. This screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC50 < 1 μM) and selectivity (SI > 10) criteria, 178 compounds progressed to the next steps where chemical diversity, physicochemical properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chemical series. A selection cascade was applied to prioritize hits resulting from the screening of a medium-sized chemical library against blood-stage P. falciparum. Emphasis was placed on chemical novelty whereby computational clustering, data mining of known anti-malarial chemotypes and the application of relaxed physicochemical filters, were key to the process. This led to the selection of 15 chemical series from which ten confirmed their activity when newly synthesized sample were tested.
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DOI：
10.1126/science.1193225
发表时间：
2010-09-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Rottmann M;McNamara C;Yeung BK;Lee MC;Zou B;Russell B;Seitz P;Plouffe DM;Dharia NV;Tan J;Cohen SB;Spencer KR;González-Páez GE;Lakshminarayana SB;Goh A;Suwanarusk R;Jegla T;Schmitt EK;Beck HP;Brun R;Nosten F;Renia L;Dartois V;Keller TH;Fidock DA;Winzeler EA;Diagana TT
通讯作者：
Diagana TT
影响因子：
7.8
作者：
Welsch, Matthew E.;Snyder, Scott A.;Stockwell, Brent R.
通讯作者：
Stockwell, Brent R.
结构引导的三唑嘧啶环取代基的铅优化鉴定出具有临床候选潜力的有效的恶性疟原虫二氢二酸二氢二酸脱氢酶抑制剂。
影响因子：
7.3
作者：
Coteron, Jose M.;Marco, Maria;Esquivias, Jorge;Deng, Xiaoyi;White, Karen L.;White, John;Koltun, Maria;El Mazouni, Farah;Kokkonda, Sreekanth;Katneni, Kasiram;Bhamidipati, Ravi;Shackleford, David M.;Angulo-Barturen, Inigo;Ferrer, Santiago B.;Belen Jimenez-Diaz, Maria;Gamo, Francisco-Javier;Goldsmith, Elizabeth J.;Charman, William N.;Bathurst, Ian;Floyd, David;Matthews, David;Burrows, Jeremy N.;Rathod, Pradipsinh K.;Charman, Susan A.;Phillips, Margaret A.
通讯作者：
Phillips, Margaret A.
DOI：
10.1073/pnas.0802982105
发表时间：
2008-07-01
影响因子：
11.1
作者：
Plouffe, David;Brinker, Achim;Winzeler, Elizabeth A.
通讯作者：
Winzeler, Elizabeth A.
影响因子：
4.2
作者：
Burrows, Jeremy N.;Leroy, Didier;Waterson, David
通讯作者：
Waterson, David