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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >An in silico structural insights into Plasmodium LytB protein and its inhibition
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An in silico structural insights into Plasmodium LytB protein and its inhibition

机译：疟原虫LytB蛋白及其抑制作用的计算机内结构洞察

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摘要

In most of the pathogenic organisms including Plasmodium falciparum, isoprenoids are synthesized via MEP (MethylErythritol 4-Phosphate) pathway. LytB is the last enzyme of this pathway which catalyzes the conversion of (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) into the two isoprenoid precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Since the MEP pathway is not used by humans, it represents an attractive target for the development of new anti-malarial compounds or inhibitors. Here a systematic in silico study has been conducted to get an insight into the structure of Plasmodium lytB as well as its affinities towards different inhibitors. We used comparative modeling technique to predict the three-dimensional (3D) structure of Plasmodium LytB taking Escherichia coli LytB protein (PDB ID: 3KE8) as template and the model was subsequently refined through molecular dynamics (MD) simulation. A large ligand data-set containing diphospate group was subjected for virtual screening against the target using GOLD 5.2 program. Considering the mode of binding and affinities, 17 leads were selected on basis of binding energies in comparison to its substrate HMBPP (Gold.Chemscore.DG: -20.9734 kcal/mol). Among them, five were discarded because of their inhibitory activity towards other human enzymes. The rest 12 potential leads carry all the properties of any "drug like" molecule and the knowledge of Plasmodium LytB-inhibitory mechanism which can provide valuable support for the anti-malarial-inhibitor design in future.
机译：在包括恶性疟原虫在内的大多数致病生物中，类异戊二烯是通过MEP（甲基赤藓糖醇4-磷酸）途径合成的。 LytB是该途径中的最后一种酶，它催化将（E）-4-羟基-3-甲基丁-2-烯-1-基二磷酸酯（HMBPP）转化为两种类异戊二烯前体：异戊烯基二磷酸酯（IPP）和二甲基烯丙基二磷酸酯（DMAPP）。由于MEP途径未被人类使用，它代表了开发新的抗疟疾化合物或抑制剂的有吸引力的目标。在这里进行了系统的计算机模拟研究，以了解疟原虫lytB的结构及其对不同抑制剂的亲和力。我们使用比较建模技术以大肠杆菌LytB蛋白（PDB ID：3KE8）为模板，预测了疟原虫LytB的三维（3D）结构，随后通过分子动力学（MD）模拟对该模型进行了完善。使用GOLD 5.2程序对包含二磷酸根基团的大型配体数据集进行针对靶标的虚拟筛选。考虑到结合方式和亲和力，与其结合底物HMBPP（Gold.Chemscore.DG：-20.9734 kcal / mol）相比，根据结合能选择了17根引线。其中，有五种因对其他人类酶的抑制活性而被丢弃。其余的12条潜在导线具有任何“药物样”分子的所有特性以及对疟原虫LytB抑制机制的知识，可以为将来的抗疟疾抑制剂设计提供有价值的支持。

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