Identification of New Human Malaria Parasite Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors by Pharmacophore and Structure-Based Virtual Screening.
Identification of New Human Malaria Parasite Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors by Pharmacophore and Structure-Based Virtual Screening.
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DOI：
10.1021/acs.jcim.5b00680
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发表时间：
2016-03-28
影响因子：
5.6
通讯作者：
Chibale K
中科院分区：
文献类型：
--
作者：
Pavadai E;El Mazouni F;Wittlin S;de Kock C;Phillips MA;Chibale K
恶性疟原虫二氢罗酸脱氢酶(PfDHODH)是恶性疟原虫赖以生存的唯一赖以生存的生物合成途径的关键酶，已成为抗疟疾药物的有效靶点。为了发现新的有效的PfDHODH抑制剂，基于已知的PfDHODH抑制剂的结构，开发了3D-QSAR药效团模型，并将验证的Hypo1模型用作虚拟筛选国家癌症研究所数据库的3D搜索查询。基于分子对接和分子力学/广义Born表面积结合能计算，进一步筛选出虚拟Hit化合物。药效团和基于结构的虚拟筛选的结合导致了9个新化合物的鉴定，表明>；其中3个化合物的IC50值在0.38~20μM之间，其中3个化合物的IC50值在0.38~20μM之间。活性最强的化合物NSC336047对PfDHODH具有种选择性，抑制寄生虫生长的IC50值为26μM。此外，有13个化合物抑制寄生虫生长，其IC50值为≤50μM，其中4个化合物的IC50值在5~12μM之间。这些化合物可用于更有效的PfDHODH和寄生虫生长抑制剂的鉴定和开发。
Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway, which the Plasmodium falciparum relies on exclusively for survival, has emerged as a promising target for antimalarial drugs. In an effort to discover new and potent PfDHODH inhibitors, 3D-QSAR pharmacophore models were developed based on the structures of known PfDHODH inhibitors and the validated Hypo1 model was used as a 3D search query for virtual screening of the National Cancer Institute database. The virtual hit compounds were further filtered based on molecular docking and Molecular Mechanics/Generalized Born Surface Area binding energy calculations. The combination of the pharmacophore and structure-based virtual screening resulted in the identification of nine new compounds that showed >25% inhibition of PfDHODH at a concentration of 10 μM, three of which exhibited IC50 values in the range of 0.38–20 μM. The most active compound, NSC336047, displayed species-selectivity for PfDHODH over human DHODH and inhibited parasite growth with an IC50 of 26 μM. In addition to this, thirteen compounds inhibited parasite growth with IC50 values of ≤ 50 μM, four of which showed IC50 values in the range of 5–12 μM. These compounds could be further explored in the identification and development of more potent PfDHODH and parasite growth inhibitors.