Department of Bioinformatics, Applied Botany Centre, University School of Sciences, Gujarat University, Ahmedabad, India.
OMICS. 2013 May;17(5):231-41. doi: 10.1089/omi.2012.0129.
It is a continuing quest to uncover the principal molecular targets of malarial parasites to understand the antimalarial activity and mechanism of action of artemisinin, a potent antimalarial. A series of parasite proteins are experimentally validated as potential targets, such as translationally controlled tumor protein (TCTP) and sarco/endoplasmic reticulum membrane calcium ATP-ase (SERCA). The present study addressed the development of a theoretical model of Plasmodium falciparum NADH dehydrogenase with inference from artemisinin in vivo inhibitory activity. We report here the predicted binding modes of artemisinin and its derivatives. The modeled protein resembled the structural architecture of flavoproteins and oxidoreductases, consisting of two Rossmann folds and dedicated binding sites for its cofactors. Docked poses of the ligand dataset revealed its interactions at or near the si face, indicating being activated. This may aid in generation of reactive oxygen species, thereby disrupting the membrane potential of parasite mitochondria and leading to the clearance from the blood. These observations open up new strategies for development of novel therapeutics, or improvement of existing pharmacotherapies against malaria, a major burden for global health.
这是一个不断探索疟原虫主要分子靶点的过程，旨在了解青蒿素这种强效抗疟药物的抗疟活性和作用机制。一系列寄生虫蛋白已被实验验证为潜在的靶标，如翻译控制肿瘤蛋白（TCTP）和肌浆/内质网膜钙 ATP 酶（SERCA）。本研究针对疟原虫 NADH 脱氢酶的理论模型进行了研究，并从青蒿素的体内抑制活性推断出结果。我们在这里报告了青蒿素及其衍生物的预测结合模式。该模型蛋白的结构架构类似于黄素蛋白和氧化还原酶，由两个 Rossmann 折叠和专门的辅因子结合位点组成。配体数据集的对接构象揭示了其在 si 面或附近的相互作用，表明其被激活。这可能有助于产生活性氧，从而破坏寄生虫线粒体的膜电位，并导致其从血液中清除。这些观察结果为开发新的治疗方法或改进现有的抗疟药物治疗方案提供了新的策略，因为疟疾是全球健康的主要负担。
