Danazumi Ammar Usman, Balogun Emmanuel Oluwadare
Faculty of Chemistry, Warsaw University of Technology, Warsaw, Poland.
Groningen Research Institute of Pharmacy, University of Groningen, Groningen, Netherlands.
Front Mol Biosci. 2022 Dec 19;9:1070080. doi: 10.3389/fmolb.2022.1070080. eCollection 2022.
The latest world malaria report revealed that human deaths caused by malaria are currently on the rise and presently stood at over 627,000 per year. In addition, more than 240 million people have the infection at any given time. These figures make malaria the topmost infectious disease and reiterate the need for continuous efforts for the development of novel chemotherapies. Malaria is an infectious disease caused majorly by the protozoan intracellular parasite and transmitted by mosquitoes. Reports abound on the central role of falcipains (cysteine protease enzymes) in the catabolism of hemoglobin for furnishing the plasmodium cells with amino acids that they require for development and survival in the hosts. Even though falcipains (FPs) have been validated as drug target molecules for the development of new antimalarial drugs, none of its inhibitory compounds have advanced beyond the early discovery stage. Therefore, there are renewed efforts to expand the collection of falcipain inhibitors. As a result, an interesting finding reported the discovery of a quinolinyl oxamide derivative (QOD) and an indole carboxamide derivative (ICD), with each compound demonstrating good potencies against the two essential FP subtypes 2 (FP-2) and 3 (FP-3). In this study, we utilized microsecond-scale molecular dynamics simulation computational method to investigate the interactions between FP-2 and FP-3 with the quinolinyl oxamide derivative and indole carboxamide derivative. The results revealed that quinolinyl oxamide derivative and indole carboxamide derivative bound tightly at the active site of both enzymes. Interestingly, despite belonging to different chemical scaffolds, they are coordinated by almost identical amino acid residues extensive hydrogen bond interactions in both FP-2 and FP-3. Our report provided molecular insights into the interactions between FP-2 and FP-3 with quinolinyl oxamide derivative and indole carboxamide derivative, which we hope will pave the way towards the design of more potent and druglike inhibitors of these enzymes and will pave the way for their development to new antimalarial drugs.
最新的《世界疟疾报告》显示，目前由疟疾导致的人类死亡人数正在上升，目前每年超过62.7万例。此外，在任何给定时间，有超过2.4亿人受到感染。这些数字使疟疾成为最主要的传染病，并再次强调了持续努力开发新型化疗方法的必要性。疟疾是一种主要由原生动物细胞内寄生虫引起、通过蚊子传播的传染病。关于疟原虫蛋白酶（半胱氨酸蛋白酶）在血红蛋白分解代谢中的核心作用的报道很多，血红蛋白分解代谢为疟原虫细胞提供其在宿主中发育和生存所需的氨基酸。尽管疟原虫蛋白酶（FPs）已被确认为开发新型抗疟疾药物的药物靶标分子，但其抑制性化合物均未超越早期发现阶段。因此，人们重新努力扩大疟原虫蛋白酶抑制剂的收集。结果，一项有趣的研究报告发现了一种喹啉基草酰胺衍生物（QOD）和一种吲哚甲酰胺衍生物（ICD），每种化合物对两种重要的FP亚型2（FP - 2）和3（FP - 3）均显示出良好的效力。在本研究中，我们利用微秒级分子动力学模拟计算方法来研究FP - 2和FP - 3与喹啉基草酰胺衍生物和吲哚甲酰胺衍生物之间的相互作用。结果表明，喹啉基草酰胺衍生物和吲哚甲酰胺衍生物紧密结合在两种酶的活性位点。有趣的是，尽管它们属于不同的化学支架，但它们在FP - 2和FP - 3中均由几乎相同的氨基酸残基通过广泛的氢键相互作用进行配位。我们的报告提供了关于FP - 2和FP - 3与喹啉基草酰胺衍生物和吲哚甲酰胺衍生物之间相互作用的分子见解，我们希望这将为设计更有效且类似药物的这些酶抑制剂铺平道路，并为将它们开发成新型抗疟疾药物铺平道路。
