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首页> 外文期刊>Dalton transactions: An international journal of inorganic chemistry >Computational insights into the inhibition of -haematin crystallization by antimalarial drugs
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Computational insights into the inhibition of -haematin crystallization by antimalarial drugs

机译：抗疟药抑制 - 抗疟药抑制抑制的洞察

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摘要

During the red blood cell phase of their life cycle, malaria parasites digest their host's haemoglobin, with concomitant release of potentially toxic iron(iii) protoporphyrin IX (FePPIX). The parasites' strategy for detoxification of FePPIX involves its crystallization to haemozoin, such that the build-up of free haem in solution is avoided. Antimalarial drugs of both historical importance and current clinical use are known to be capable of disrupting the growth of crystals of -haematin, which is the synthetic equivalent of haemozoin. Hence, the disruption of haemozoin crystal growth is implicated as a possible mode of action of such drugs. However, the details of -haematin crystal poisoning at the molecular level have yet to be fully elucidated. In this study, we have used a combination of density functional theory (DFT) and molecular modelling to examine the possible modes of action of ten different antimalarial drugs, including quinine-type aliphatic alcohols, amodiaquine-type phenols, and chloroquine-type aliphatic diamines. The DFT calculations indicate that each of the drugs can form at least one molecular complex with FePPIX. These complexes have 1:1 or 2:1 FePPIX:drug stoichiometries and all of them incorporate Fe-O bonds, formed either by direct coordination of a zwitterionic form of the drug, or by deprotonation of water. Most of the drugs can form more than one such complex. We have used the DFT model structures to explore the possible formation of a monolayer of each drug-haem complex on four of the -haematin crystal faces. In all cases, the drug complexes can form a monolayer on the fast-growing {001} and {011} faces, but not on the slower growing {010} and {100} faces. Additional modelling of the chloroquine and quinidine complexes shows that individual molecules of these species can also obstruct the growth of new layers on other crystal faces. The implications of these observations for antimalarial drug development are discussed.
机译：在其生命周期的红细胞阶段，疟原虫消化其宿主的血红蛋白，具有原卟啉IX（FePPIX）具有潜在毒性的铁（III）的伴随释放。寄生虫为FePPIX的解毒战略涉及其结晶疟色素，从而在溶液中积聚免费血红素的是可以避免的。的两个历史重要性和目前临床使用的抗疟疾药物是已知的能够破坏-haematin的晶体的生长，这是疟色素的合成等价的。因此，疟色素晶体生长的破坏牵涉作为这类药物的作用的一种可能的模式。然而，-haematin水晶中毒在分子水平上的细节尚未完全阐明。在这项研究中，我们已经使用密度泛函理论（DFT）和分子建模的组合来检查的十个不同的抗疟疾药物，包括奎宁型的脂族醇，阿莫地喹型酚和氯喹型脂肪族二胺动作的可能的模式。在DFT计算表明，每种药物可以形成具有FePPIX至少一种分子复合物。这些复合物具有1：1或2：1 FePPIX：药物的化学计量和它们全部并入的Fe-O键，通过将药物的两性离子形式的直接协调形成任一，或通过去质子化水。大多数药物可形成一个以上这种复杂的。我们已经使用了DFT模型结构，以探索对-haematin晶面的四个可能的形成每种药物血红素复合物的单层。在所有情况下，药物复合物可以形成对快速增长的{001}和{011}面的单层，但不是在较慢的生长{010}和{100}面。的氯喹和奎尼丁配合物表明，这些物质的单个分子还可以阻碍的新的层上的其他晶面的生长额外建模。这些看法对抗疟疾药物发展的影响进行了讨论。

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