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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Targeting metacaspase-3 from Plasmodium falciparum towards antimalarial therapy: A combined approach of in-silico and in-vitro investigation
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Targeting metacaspase-3 from Plasmodium falciparum towards antimalarial therapy: A combined approach of in-silico and in-vitro investigation

机译：从疟原虫对抗疟疾治疗的靶向Metacaspase-3：硅藻土和体外调查的组合方法

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Malaria is a global challenge, and its infection is propagated through Plasmodium falciparum, an obligate human parasite. The genome of P. falciparum encodes many proteases that play significant roles in their survival and pathogenesis thus being considered as attractive drug targets. P. falciparum metacaspase-3 (PfMCA3) is one such protease and a validated drug target to control malarial infection. First, we modeled the three-dimensional structure of PfMCA3 and predicted its ligand-binding pocket. The structural features of PfMCA3 were used for virtual screening followed by docking and molecular dynamics (MD) simulation studies to identify potent inhibitors. We used an in-house library of 513 compounds for screening to identify lead molecule fits well in the active site pocket of PfMCA3. The binding affinity and mechanism were investigated by combined docking and MD simulation studies. Docking studies reveal that the selected compounds are forming enough number of non-covalent interactions to the PfMCA3. In the enzyme inhibition assay, one of the selected compounds, H6 was found with appreciable inhibitory potential. MD simulation studies further support the binding of compound H6 with PfMCA3 and formation of a stable complex throughout the simulation trajectory. Taken together, we proposed that compound H6 is a promising lead scaffold that can be further exploited as a potential inhibitor of PfMCA3 for therapeutic management of malarial infection. Communicated by Ramaswamy H. Sarma
机译：疟疾是一个全球性的挑战，其感染通过恶性疟原虫（一种专性人类寄生虫）传播。恶性疟原虫基因组编码许多蛋白酶，这些蛋白酶在其生存和发病机制中发挥重要作用，因此被认为是有吸引力的药物靶点。恶性疟原虫metacaspase-3（PfMCA3）就是这样一种蛋白酶，也是控制疟疾感染的有效药物靶点。首先，我们模拟了PfMCA3的三维结构，并预测了其配体结合口袋。PfMCA3的结构特征用于虚拟筛选，然后进行对接和分子动力学（MD）模拟研究，以确定有效的抑制剂。我们使用513种化合物的内部文库进行筛选，以确定铅分子与PfMCA3的活性位点口袋非常吻合。结合对接和分子动力学模拟研究了其结合亲和力和机制。对接研究表明，所选化合物与PfMCA3形成了足够数量的非共价相互作用。在所选化合物之一的酶抑制试验中，发现H6具有明显的抑制潜力。MD模拟研究进一步支持化合物H6与PfMCA3的结合，并在整个模拟轨迹中形成稳定的复合物。综上所述，我们认为化合物H6是一种很有前途的铅支架材料，可以作为PfMCA3的潜在抑制剂进一步开发，用于疟疾感染的治疗管理。由拉玛斯瓦米·H·萨尔玛传达

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