The invasive tactics employed by the malarial parasite renders malaria a global health threat, further impeding the effective treatment of the mosquito borne-parasitic disease. Although there have been countless efforts directed towards the development of effective therapeutics, factors such as emerging strains of drug resistance, enhanced toxicity and poor pharmacokinetic properties of current therapeutics has hampered the drug discovery process resulting in the spread of this parasitic disease. A promising target of the most lethal strain of the Plasmodium species that plays a predicted role in erythrocyte invasion of the virulent malarial parasite is aspartic protease IX commonly referred to Plasmepsin IX. The integration of computer aided-drug design platforms has revolutionized the 21st century and has opened avenues to render a final “knock out” in the elimination and eradication of this parasitic disease Hitherto, this is the first attempt directed towards the design of therapeutics tailored explicitly to Plasmepsin IX. A potent peptidomimetic inhibitor referred to as 49c which is a known inhibitor of Plasmepsin II, has recently exhibited potent inhibitory activity against Plasmepsin IX. In-silico structural and physicochemical inspection of 49c displayed poor pharmacokinetic properties thus paving the way for the development of tailored inhibitors with desirable therapeutic properties against Plasmepsin IX. In this study we implement the pharmacophore model approach in combination with per-residue energy decomposition analysis to serve as a powerful cornerstone, that may assist medicinal experts in the composition of multifunctional therapeutics that may predispose factors such as cross-resistance and toxicity, with enhanced pharmacokinetic properties.

中文翻译：

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揭开疟疾治疗学的新纪元：针对纤溶酶IX抑制剂设计的量身定制分子方法。

疟疾寄生虫采用的侵入性策略使疟疾成为全球健康威胁，进一步阻碍了对蚊媒寄生虫病的有效治疗。尽管已经进行了无数努力来开发有效的治疗剂，但是诸如新出现的抗药性菌株，增强的毒性和当前治疗剂的不良药代动力学特性等因素阻碍了导致这种寄生虫病传播的药物发现过程。最致命的疟原虫菌株的有希望的目标在有毒的疟疾寄生虫的红细胞侵袭中发挥预测作用的细菌是天冬氨酸蛋白酶IX，通常称为溶血素IX。计算机辅助药物设计平台的集成已经彻底改变了21世纪，并为消除和消除这种寄生虫病打开了最终的“大门”，这是迄今为止，这是针对明确设计的治疗剂设计的首次尝试。蛋白酶9。一种有效的拟肽抑制剂，称为49c，它是纤溶酶II的已知抑制剂，最近表现出对纤溶酶IX的有效抑制活性。在计算机上对49c进行的结构和物理化学检查显示出不良的药代动力学特性，从而为开发具有理想的抗纤溶酶IX抑制剂的定制化抑制剂铺平了道路。在这项研究中，我们将药效团模型方法与每个残基的能量分解分析结合起来，作为一个强大的基石，可以帮助医学专家构建可能具有诸如交叉耐药性和毒性等因素的多功能疗法，并增强药代动力学特性。