Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I-IV in view of the interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations is analyzed.

译文

:胃蛋白酶是天冬氨酸蛋白酶,参与宿主细胞血红蛋白的降解,被疟原虫用作食物来源。纤溶酶作为药物靶标非常有前途,特别是与抑制也与血红蛋白分解代谢有关的falcipains结合使用时。在这篇综述中,我们鉴于对过渡态模拟物作为潜在的潜在铅化合物的发展感兴趣,讨论了纤溶酶I-IV的机制。概述了针对纤溶酶II的抑制剂的开发以及相关的晶体结构,以便对该领域进行概述。计算技术的应用,特别是通过线性相互作用能法的结合亲和力预测,在疟疾纤溶酶抑制剂的开发中已经取得了很大的成功,并进行了详细的讨论。均相建模和分子对接在当前的抑制剂设计项目中非常有用,并且分析了这些方法与结合自由能计算的结合。

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