Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
Protein J. 2019 Dec;38(6):616-627. doi: 10.1007/s10930-019-09871-2.
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.
疟原虫采用的侵袭策略使其成为全球健康威胁，进一步阻碍了对这种由蚊子传播的寄生虫病的有效治疗。尽管人们已经做出无数努力来开发有效的治疗方法，但由于出现了耐药菌株、增强的毒性以及当前治疗方法的药代动力学特性不佳等因素，阻碍了药物发现过程，导致这种寄生虫病的传播。疟原虫物种中最致命菌株的一个有前途的靶点是天冬氨酸蛋白酶 IX，通常称为 Plasmepsin IX，它在恶性疟原虫的红细胞入侵中发挥预测作用。计算机辅助药物设计平台的整合彻底改变了 21 世纪，并为消除和根除这种寄生虫病开辟了道路。迄今为止，这是首次针对专门针对 Plasmepsin IX 设计治疗方法的尝试。一种称为 49c 的有效肽模拟抑制剂是 Plasmepsin II 的已知抑制剂，最近对 Plasmepsin IX 表现出了很强的抑制活性。对 49c 的计算机结构和物理化学检查显示其药代动力学特性较差，因此为开发针对 Plasmepsin IX 的具有理想治疗特性的定制抑制剂铺平了道路。在这项研究中，我们结合残基能量分解分析实施药效团模型方法，作为一个强大的基石，可能有助于医学专家组成多功能治疗药物，这些药物可能会带来交叉耐药性和毒性等因素，并增强药代动力学特性。
