Background: Plasmodium falciparum is the most dangerous and widespread diseasecausing species of malaria. Falcipain-2 (FP2) of Plasmodium falciparum, is a potential target for antimalarial chemotherapy since it is involved in an essential cellular function such as hemoglobin degradation during the parasite’s life cycle. However, despite their central role in the life cycle of the parasite, no commercial drug targeting Falcipain-2 has been developed to date. Prior efforts to develop peptide-based drugs against Plasmodium have been futile due to their susceptibility to being degraded by host enzymes.

Objective: Here, we report computer-aided drug design of new nonpeptidic inhibitors against FP2, which are likely to be safe from degradation by host enzymes.

Methods: We have virtually screened for the probable FP2 inhibitors from the PubChem database by submitting the well-equilibrated 3-D structure of FP2. Furthermore, virtual screenings and dockings were carried out using PyRx and Discovery Studio.

Results: We found 15 top-ranking molecules with carbaldehyde pharmacophore having a good fit with the target protein. Based on the C-Docker values, the top 4 hits (PubChem 44138738, Pub- Chem 20983198, PubChem 20983081 and PubChem 28951461) for FP2 were identified. These four hits have been observed to bound to the active cleft of the protein. Moreover, their complexes were also found to be stable from the RMSD and Radius of Gyration analysis.

Conclusion: The selected compounds 2-(benzylamino)-8-methylquinoline-3-carbaldehyde (Pub- Chem44138738), 6-bromo-2-(3,4-dihydro-1H-isoquinolin-2-yl)quinoline-3-carbaldehyde (Pub- Chem 20983198), 2-(3,4-dihydro-1H-isoquinolin-2-yl)-6-ethylquinoline-3-carbaldehyde(PubChem 20983081)and 2-[benzyl(methyl)amino]quinoline-3-carbaldehyde (PubChem 28951461) may be the starting point for further modification as a new type of nonpeptidic drug for malaria disease.

背景：恶性疟原虫是最危险和最普遍的疟疾致病物种。恶性疟原虫的 Falcipain-2 (FP2) 是抗疟化疗的潜在靶标，因为它参与寄生虫生命周期中的基本细胞功能，例如血红蛋白降解。然而，尽管它们在寄生虫的生命周期中发挥着核心作用，但迄今为止尚未开发出针对 Falcipain-2 的商业药物。先前开发针对疟原虫的基于肽的药物的努力是徒劳的，因为它们容易被宿主酶降解。

目的：在这里，我们报告了针对 FP2 的新型非肽抑制剂的计算机辅助药物设计，这些抑制剂可能不会被宿主酶降解。

方法：我们通过提交 FP2 的平衡良好的 3-D 结构，从 PubChem 数据库中虚拟筛选出可能的 FP2 抑制剂。此外，使用 PyRx 和 Discovery Studio 进行了虚拟放映和对接。

结果：我们发现 15 个具有甲醛药效团的顶级分子与靶蛋白具有良好的拟合度。根据 C-Docker 值，确定了 FP2 的前 4 个命中（PubChem 44138738、PubChem 20983198、PubChem 20983081 和 PubChem 28951461）。已观察到这四个命中与蛋白质的活性裂隙结合。此外，通过 RMSD 和回转半径分析，还发现它们的配合物是稳定的。

结论：所选化合物 2-(benzylamino)-8-methylquinoline-3-carbaldehyde (Pub-Chem44138738), 6-bromo-2-(3,4-dihydro-1H-isoquinolin-2-yl)quinoline-3-carbaldehyde (Pub- Chem 20983198)、2-(3,4-dihydro-1H-isoquinolin-2-yl)-6-ethylquinoline-3-carbaldehyde(PubChem 20983081) 和 2-[苄基(甲基)氨基]喹啉-3-甲醛（PubChem 28951461）可能是进一步修饰为治疗疟疾的新型非肽类药物的起点。