当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Identification of Selective Inhibitors of Plasmodium N-Myristoyltransferase by High-Throughput Screening.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-08 , DOI: 10.1021/acs.jmedchem.9b01343 Anke Harupa 1, 2, 3 , Laura De Las Heras 2 , Gonzalo Colmenarejo 2 , Sally Lyons-Abbott 1, 4 , Alexandra Reers 1, 4, 5 , Iván Caballero Hernandez 2 , Chun-Wa Chung 2 , David Charter 2 , Peter J Myler 1, 4, 5 , Raquel M Fernández-Menéndez 2 , Félix Calderón 2 , Sara Palomo 2 , Beatriz Rodríguez 2 , Manuela Berlanga 2 , Esperanza Herreros-Avilés 2 , Bart L Staker 1, 4, 5 , Elena Fernández Álvaro 2 , Alexis Kaushansky 1, 5, 6
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-08 , DOI: 10.1021/acs.jmedchem.9b01343 Anke Harupa 1, 2, 3 , Laura De Las Heras 2 , Gonzalo Colmenarejo 2 , Sally Lyons-Abbott 1, 4 , Alexandra Reers 1, 4, 5 , Iván Caballero Hernandez 2 , Chun-Wa Chung 2 , David Charter 2 , Peter J Myler 1, 4, 5 , Raquel M Fernández-Menéndez 2 , Félix Calderón 2 , Sara Palomo 2 , Beatriz Rodríguez 2 , Manuela Berlanga 2 , Esperanza Herreros-Avilés 2 , Bart L Staker 1, 4, 5 , Elena Fernández Álvaro 2 , Alexis Kaushansky 1, 5, 6
Affiliation
|
New drugs that target Plasmodium species, the causative agents of malaria, are needed. The enzyme N-myristoyltransferase (NMT) is an essential protein, which catalyzes the myristoylation of protein substrates, often to mediate membrane targeting. We screened ∼1.8 million small molecules for activity against Plasmodium vivax (P. vivax) NMT. Hits were triaged based on potency and physicochemical properties and further tested against P. vivax and Plasmodium falciparum (P. falciparum) NMTs. We assessed the activity of hits against human NMT1 and NMT2 and discarded compounds with low selectivity indices. We identified 23 chemical classes specific for the inhibition of Plasmodium NMTs over human NMTs, including multiple novel scaffolds. Cocrystallization of P. vivax NMT with one compound revealed peptide binding pocket binding. Other compounds show a range of potential modes of action. Our data provide insight into the activity of a collection of selective inhibitors of Plasmodium NMT and serve as a starting point for subsequent medicinal chemistry efforts.
中文翻译：
通过高通量筛选鉴定疟原虫N-肉豆蔻酰基转移酶的选择性抑制剂。
需要针对疟原虫物种的新药物，疟疾的病原体。N-肉豆蔻酰基转移酶（NMT）是必需的蛋白质，它催化蛋白质底物的肉豆蔻酰基化，通常介导膜靶向。我们筛选了约180万个针对间日疟原虫（间日疟原虫）NMT活性的小分子。根据效价和理化性质对命中进行分类，并针对间日疟原虫和恶性疟原虫（恶性疟原虫）NMT进行进一步测试。我们评估了针对人类NMT1和NMT2的命中活性以及丢弃的具有低选择性指数的化合物。我们确定了23种化学特异于人类NMT抑制疟原虫NMT的化学类别，包括多个新型支架。间日疟原虫NMT与一种化合物的共结晶揭示了肽结合口袋结合。其他化合物显示出一系列潜在的作用方式。我们的数据提供了对疟原虫NMT选择性抑制剂集合的活性的见解，并为后续药物化学工作提供了起点。
更新日期：2020-01-08
中文翻译：
通过高通量筛选鉴定疟原虫N-肉豆蔻酰基转移酶的选择性抑制剂。
需要针对疟原虫物种的新药物，疟疾的病原体。N-肉豆蔻酰基转移酶（NMT）是必需的蛋白质，它催化蛋白质底物的肉豆蔻酰基化，通常介导膜靶向。我们筛选了约180万个针对间日疟原虫（间日疟原虫）NMT活性的小分子。根据效价和理化性质对命中进行分类，并针对间日疟原虫和恶性疟原虫（恶性疟原虫）NMT进行进一步测试。我们评估了针对人类NMT1和NMT2的命中活性以及丢弃的具有低选择性指数的化合物。我们确定了23种化学特异于人类NMT抑制疟原虫NMT的化学类别，包括多个新型支架。间日疟原虫NMT与一种化合物的共结晶揭示了肽结合口袋结合。其他化合物显示出一系列潜在的作用方式。我们的数据提供了对疟原虫NMT选择性抑制剂集合的活性的见解，并为后续药物化学工作提供了起点。
京公网安备 11010802027423号