Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
Department of Biomedical Engineering, School of Engineering Sciences, University of Ghana, Accra, Ghana.
Front Cell Infect Microbiol. 2022 May 25;12:868529. doi: 10.3389/fcimb.2022.868529. eCollection 2022.
Recent reports of resistance to artemisinin-based combination drugs necessitate the need to discover novel antimalarial compounds. The present study was aimed at identifying novel antimalarial compounds from natural product libraries using computational methods. is highly dependent on the pyrimidine biosynthetic pathway, a pathway responsible for the production of pyrimidines, and the parasite lacks the pyrimidine salvage enzymes. The thymidylate monophosphate kinase (TMPK) is an important protein necessary for rapid DNA replication; however, due to its broad substrate specificity, the protein is distinguished from its homologs, making it a suitable drug target. Compounds from AfroDB, a database of natural products originating from Africa, were screened virtually against TMPK after filtering the compounds for absorption, distribution, metabolism, excretion, and toxicity (ADMET)-acceptable compounds with FAF-Drugs4. Thirteen hits with lower binding energies than thymidine monophosphate were selected after docking. Among the thirteen compounds, ZINC13374323 and ZINC13365918 with binding energies of -9.4 and -8.9 kcal/mol, respectively, were selected as plausible lead compounds because they exhibited structural properties that ensure proper binding at the active site and inhibitory effect against TMPK. ZINC13374323 (also called aurantiamide acetate) is known to exhibit anti-inflammatory and antiviral activities, and ZINC13365918 exhibits antileishmanial activity. Furthermore, aurantiamide acetate, which is commercially available, is a constituent of , the herb from which artemisinin was derived. The compound also shares interactions with several residues with a potent thymidine analog inhibitor of TMPK. The anti-plasmodial activity of aurantiamide acetate was evaluated , and the mean half-maximal inhibitory concentration (IC) was 69.33 μM when synchronized 3D7 culture was used as compared to IC > 100 μM with asynchronized culture. The significance of our findings within the context of malaria treatment strategies and challenges is discussed.
最近有报道称，青蒿素类联合药物出现了耐药性，因此有必要发现新的抗疟化合物。本研究旨在使用计算方法从天然产物库中鉴定新的抗疟化合物。疟原虫对嘧啶生物合成途径高度依赖，该途径负责嘧啶的产生，而寄生虫缺乏嘧啶补救酶。胸苷单磷酸激酶（TMPK）是快速 DNA 复制所必需的重要蛋白质；然而，由于其广泛的底物特异性，该蛋白与其同源物区分开来，使其成为一个合适的药物靶点。来自非洲天然产物数据库 AfroDB 的化合物经过吸收、分布、代谢、排泄和毒性（ADMET）可接受性筛选后，虚拟筛选 TMPK。对接后，选择了 13 种结合能低于胸苷单磷酸的化合物。在这 13 种化合物中，结合能分别为-9.4 和-8.9 kcal/mol 的 ZINC13374323 和 ZINC13365918 被选为合理的先导化合物，因为它们具有确保在活性部位正确结合和抑制 TMPK 的结构特性。ZINC13374323（也称为aurantiamide 乙酸盐）已知具有抗炎和抗病毒活性，ZINC13365918 具有抗利什曼原虫活性。此外，aurantiamide 乙酸盐是一种商业上可获得的物质，是青蒿素的草药的组成部分。该化合物还与 TMPK 的几种强效胸苷类似物抑制剂的残基相互作用。当使用同步 3D7 培养物时，评估了 aurantiamide 乙酸盐的抗疟原虫活性，其平均半最大抑制浓度（IC）为 69.33 μM，而在非同步培养物中，IC > 100 μM。讨论了我们的发现在疟疾治疗策略和挑战方面的意义。
