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首页> 外文期刊>Computational Chemistry >Computational Study of the Interactions between Antimalarial Chemotherapies with Folate Pathway Receptors and Telomerase Reverse Transcriptase
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Computational Study of the Interactions between Antimalarial Chemotherapies with Folate Pathway Receptors and Telomerase Reverse Transcriptase

机译：叶酸途径受体和端粒酶逆转录酶抗疟性化学疗法相互作用的计算研究

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Malaria is a life-threatening disease responsible for half a million death annually, and with nearly half of the world’s population at risk. The rapid drop in observed cases of malaria in the last two decades has been due to a combination of preventive and therapeutic remedies. However, the absence of a vaccine, new antimalarial chemotherapies and increased parasitic resistance have led to a plateau of infections and renewed research interest in target human and Plasmodium (the malaria parasite) receptors and new drugs. In this study, the impact of mutation on the affinity on antimalarial drugs with the bifunctional enzyme complex, dihydrofolate reductase (DHFR) is explored. In addition, homology modeling is used to build the three-dimensional models of the enzymes Plasmodium telomerase reverse-transcriptase ( pf-TERT ) and Plasmodium dihydropteroate synthetase ( pf-DHPS ) to determine their affinity with antimalarial drugs. The interaction energies and stable complexes formed between these enzymes and antimalarial drugs (chloroquine, artemisinin, primaquine, pyrimethamine, sulfadoxine and pentamidine) were modelled using AutoDock vina. Our data indicate that pf-TERT and pf-DHPS form stable complexes with the antimalarial ligands with affinity ranging from &#8722 4.0 to &#8722 6.9 kcal/mol. The affinity with crystal structures of DHFR receptors was higher ranging from &#8722 6.0 to &#8722 10.0 kcal/mol. The affinity to DHFR also decreases with the mutation a confirmation of the source of resistance. The highest affinity interaction for all the receptors modeled is observed with Artemisinin a benchmark antimalarial drug. This can be attributed to the size, shape and dipolar surface of the ligand. The observed complexes are stabilized by strategic active site polar and non-polar contacts.
机译：疟疾是一项危及生命的疾病，每年负责百万分之一的死亡，并拥有近一半的世界人口风险。过去二十年来观察到的疟疾病例的迅速下降是由于预防性和治疗补救措施的组合。然而，没有疫苗，新的抗疟疾化疗和增加的寄生抗性导致了对靶人和疟原虫（疟疾寄生虫）受体和新药的靶心和再次研究兴趣的高原。在这项研究中，探讨了突变对抗疟药与双官能酶复合物的亲和力的影响，探讨了二氢酚酸还原酶（DHFR）。此外，使用同源性建模用于构建酶疟原虫酶反转转录酶（PF-TERT）和疟原型二氢化酸盐合成酶（PF-DHP）的三维模型，以确定它们与抗疟药的亲和力。使用Autodock Vina模型在这些酶和抗疟药中形成的相互作用能和稳定的复合物（氯喹，氯喹，丙氨酸，嘧啶，嘧丁胺，磺酰胺和芬太丁）。我们的数据表明PF-TERT和PF-DHPS与具有亲和范围的抗疟配体的稳定复合物，从＆amp;＃8722 4.0至＆amp;＃8722 6.9 kcal / mol。与＆amp的DHFR受体的晶体结构的亲和力较高。＃8722 6.0至＆amp;＃8722 10.0 kcal / mol。对DHFR的亲和力也随着突变进行抗性的确认而降低。用青蒿素的基准抗疟药剂观察到所有受体的最高亲和力相互作用。这可以归因于配体的尺寸，形状和偶极表面。观察到的复合物通过战略性活性位点极性和非极性触点稳定。

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