Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban 4001, South Africa.
Department of Industrial and Health Sciences, Faculty of Applied Sciences, Takoradi Technical University, Takoradi 256, Ghana.
Molecules. 2022 Nov 16;27(22):7915. doi: 10.3390/molecules27227915.
The past decade has seen most antimalarial drugs lose their clinical potency stemming from parasite resistance. Despite immense efforts by researchers to mitigate this global scourge, a breakthrough is yet to be achieved, as most current malaria chemotherapies suffer the same fate. Though the etiology of parasite resistance is not well understood, the parasite's complex life has been implicated. A drug-combination therapy with artemisinin as the central drug, artemisinin-based combination therapy (ACT), is currently the preferred malaria chemotherapy in most endemic zones. The emerging concern of parasite resistance to artemisinin, however, has compromised this treatment paradigm. Membrane-bound Ca-transporting ATPase and endocytosis pathway protein, Kelch13, among others, are identified as drivers in plasmodium parasite resistance to artemisinin. To mitigate parasite resistance to current chemotherapy, computer-aided drug design (CADD) techniques have been employed in the discovery of novel drug targets and the development of small molecule inhibitors to provide an intriguing alternative for malaria treatment. The evolution of plasmepsins, a class of aspartyl acid proteases, has gained tremendous attention in drug discovery, especially the non-food vacuole. They are expressed at multi-stage of the parasite's life cycle and involve in hepatocytes' egress, invasion, and dissemination of the parasite within the human host, further highlighting their essentiality. In silico exploration of non-food vacuole plasmepsin, PMIX and PMX unearthed the dual enzymatic inhibitory mechanism of the WM382 and 49c, novel plasmepsin inhibitors presently spearheading the search for potent antimalarial. These inhibitors impose structural compactness on the protease, distorting the characteristic twist motion. Pharmacophore modeling and structure activity of these compounds led to the generation of hits with better affinity and inhibitory prowess towards PMIX and PMX. Despite these headways, the major obstacle in targeting PM is the structural homogeneity among its members and to human Cathepsin D. The incorporation of CADD techniques described in the study at early stages of drug discovery could help in selective inhibition to augment malaria chemotherapy.
过去十年，大多数抗疟药物因寄生虫耐药性而失去临床疗效。尽管研究人员做出了巨大努力来减轻这一全球性灾难，但尚未取得突破，因为大多数当前的疟疾化疗药物都面临着同样的命运。尽管寄生虫耐药性的病因尚不清楚，但寄生虫的复杂生活方式已被牵连其中。青蒿素为中心药物的药物联合疗法，即青蒿素为基础的联合疗法（ACT），目前是大多数流行地区首选的疟疾化疗方法。然而，寄生虫对青蒿素耐药性的出现，已经影响了这种治疗模式。膜结合钙转运 ATP 酶和内吞途径蛋白 Kelch13 等被认为是疟原虫对青蒿素耐药性的驱动因素。为了减轻寄生虫对当前化疗药物的耐药性，计算机辅助药物设计（CADD）技术已被用于发现新的药物靶点和开发小分子抑制剂，为疟疾治疗提供了一种有趣的替代方法。一类天冬氨酸蛋白酶类的类胰蛋白酶的进化，在药物发现中引起了极大的关注，尤其是非食物液泡。它们在寄生虫生命周期的多个阶段表达，并参与肝细胞的逸出、入侵和寄生虫在人体宿主中的传播，进一步强调了它们的重要性。非食物液泡类胰蛋白酶 PMIX 和 PMX 的计算机探索揭示了 WM382 和 49c 的双重酶抑制机制，这两种新型类胰蛋白酶抑制剂目前正在寻找强效抗疟药物。这些抑制剂使蛋白酶结构紧凑，扭曲了其特征性扭曲运动。这些化合物的药效基团模型和结构活性研究导致了具有更好亲和力和抑制作用的化合物的生成，这些化合物对 PMIX 和 PMX 具有更好的亲和力和抑制作用。尽管取得了这些进展，但靶向 PM 的主要障碍是其成员和人组织蛋白酶 D 之间的结构同质性。在药物发现的早期阶段采用 CADD 技术，可以帮助进行选择性抑制，以增强疟疾化疗效果。
