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首页> 外文期刊>Journal of vector borne diseases. >Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: A structure-based drug designing approach
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Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: A structure-based drug designing approach

机译：针对恶性激素III设计新型抗疟疾药物的基于计算的虚拟筛选：一种基于结构的药物设计方法

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Background & objectives: Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Methods: Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. Results: The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having better binding affinity compared to the PDB bound inhibitor of falcipain-III. The docking simulation results of falcipain-III with designed leupeptin analogues using Glide compared with AutoDock and find 80% similarity as better binder than leupeptin. Interpretation & conclusion: These results further highlight new leupeptin analogues as promising future inhibitors for chemotherapeutic prevention of malaria. The result of Glide for falcipain-III has been compared with the result of AutoDock and finds very less differences in their order of binding affinity. Although there are no extra hydrogen bonds, however, equal number of hydrogen bonds with variable strength as compared to leupeptin along with the enhanced hydrophobic and electrostatic interactions in case of analogues supports our study that it holds the ligand molecules strongly within the receptor. The comparative e-pharmacophoric study also suggests and supports our predictions regarding the minimum features required in ligand molecule to behave as falcipain- III inhibitors and is also helpful in screening the large database as future antimalarial inhibitors.
机译：背景与目标：半胱氨酸蛋白酶（falcipains）是恶性疟原虫酶的木瓜蛋白酶家族，负责血红蛋白的降解，因此对于人类红细胞内部无性生命周期阶段的生存是必需的，同时对人类仍然无功能身体。因此，这些可以作为设计抗疟药的潜在目标。恶性疟原虫半胱氨酸蛋白酶，恶性疟原-II和恶性疟原-III是引发血红蛋白降解的酶，因此已被选为靶标。在本研究中，我们设计了新的亮肽素类似物，并在Falcipain-II和Falcipain-III的活性部位腔内使用Glide进行了虚拟筛选，以根据Glide评分选择最佳的对接类似物，并与之比较。 AutoDock。拟议的类似物可作为未来有效的抗疟药进行合成和体内测试。方法：分别从蛋白质数据库（PDB）中检索出蛋白质falcipain-II和falcipain-III以及结合抑制剂环氧丁二酸E64（E64）和Leupeptin，然后将后者以Leupeptin为先导分子，使用Ligbuilder软件设计新的类似物并对其进行精制分子基于Lipinski五规则和适应度得分参数。通过使用Glide软件和AutoDock在falcipain-II和falcipain-III的活性位点对接模拟，筛选了所有设计的亮肽素类似物。结果：在Ligbuilder的帮助下，采用基于结构的药物设计方法，设计了104种新的基于亮肽素的抗疟原体，并通过对接模拟方法对falcipain-II和falcipain-III受体蛋白进行了虚拟筛选。滑翔对接结果表明，配体即result_037表现出良好的结合，而另两种，result_044和result_042表现出与天然存在的PDB结合配体E64对falcipain-II几乎相似的结合，在falcipain-III的情况下，设计的15种亮肽素类似物具有更好的结合与PDB结合的Falcipain-III抑制剂相比具有更高的亲和力。与AutoDock相比，使用Glide与设计的亮肽素类似物对接的恶性肽III的对接模拟结果发现，与亮肽素相比，更好的结合剂具有80％的相似性。解释与结论：这些结果进一步突显了新的亮肽素类似物作为有希望的未来化学疗法预防疟疾的抑制剂。将Glide for falcipain-III的结果与AutoDock的结果进行了比较，发现它们在结合亲和力方面的差异非常小。尽管没有多余的氢键，但是，与亮肽素相比，具有相等强度的氢键数量可变，并且在类似物的情况下疏水和静电相互作用增强，这支持了我们的研究，即其将配体分子牢固地保留在受体内。对比电子药效学研究还建议并支持我们有关配体分子起恶性激素III抑制剂作用的最低特征的预测，并且有助于筛选大型数据库作为未来的抗疟疾抑制剂。

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