Identification of novel Plasmodium falciparum dihydroorotate dehydrogenase inhibitors for malaria using in silico studies
Identification of novel Plasmodium falciparum dihydroorotate dehydrogenase inhibitors for malaria using in silico studies
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DOI：
10.1016/j.sciaf.2022.e01214
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发表时间：
2022-05-10
影响因子：
2.9
通讯作者：
Elbadwi, Fatima A.
中科院分区：
文献类型：
--
作者：
Alzain, Abdulrahim A.;Ahmed, Zain Alsharf M.;Elbadwi, Fatima A.
疟疾是一种古老的传染病，由于其高传染性和高死亡率而被认为是一个严重的健康问题。更有害的疟疾是恶性疟原虫（Pf），每年造成超过100万人死亡;不幸的是，现有的药物治疗方案受到耐药性的阻碍，需要确定针对疟原虫物种的新靶标。由于疟原虫不能回收嘧啶，它必须依靠从头生产来生存。因此，促进该过程的限速阶段的二氢乳清酸脱氢酶（DHODH）是一个有趣的抗疟靶点。在这种情况下，进行包括药效团作图、分子对接、MM-GBSA计算、ADME过滤和分子动力学的计算筛选，以鉴定新型和强效的PfDHODH抑制剂。创建了具有七个特征的药效团假设，并对来自烯胺数据库的200万种化合物进行了测试。对接、MM-GBSA计算和ADME揭示了10个具有强结合亲和力和潜力、稳定结合能和药物样性质的命中。使用分子动力学模拟进一步确认了前三个命中，这表明其中三个在整个100 ns模拟时间内是稳定的。根据这些发现，我们建议提交Z1481646084、Z24317941和Z951873618作为有前景的抗疟药进行实验验证。(c)2022作者（S）由Elsevier B. V.代表非洲数学科学研究所/下一个爱因斯坦倡议出版。这是一个在CC BY许可证下的开放获取文章（http://creativecommons.org/licenses/by/4.0/）
Malaria, that ancient infectious disease is considered a great health problem due to its highly infectious and mortality rates. The more harmful kind of malaria is Plasmodium falciparum (Pf), accounting for over 1M fatalities yearly; unfortunately, existing medication regimens are hampered by resistance, necessitating the identification of novel targets against plasmodium species. Since the malaria parasite cannot recover pyrimidines, it must rely on de novo production to survive. Dihydroorotate dehydrogenase (DHODH), which facilitates the rate-limiting phase of that process, is therefore an interesting antimalarial target. In this context, computational screening comprising pharmacophore mapping, molecular docking, MM-GBSA calculations, ADME filtering and molecular dynamics were performed in order to identify novel and powerful PfDHODH inhibitors. A pharmacophore hypothesis with seven features was created and tested on 2 million compounds from the enamine database. Docking, MM-GBSA calculations, and ADME revealed ten hits with strong binding affinities and potential, stable binding energy, and drug-like properties. The top three hits were confirmed further using molecular dynamics simulations, which revealed that three of them were stable for the whole 100 ns simulation time. Relying on these findings, we recommend that Z1481646084, Z24317941, and Z951873618 be submitted for experimental verification as promising antimalarial gents.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of African Institute of Mathematical Sciences / Next Einstein Initiative. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )