BACKGROUND The Plasmodium falciparum M18 Aspartyl Aminopeptidase (PfM18AAP) is only aspartyl aminopeptidase which is found in the genome of P. falciparum and is essential for its survival. The PfM18AAP enzyme performs various functions in the parasite and the erythrocytic host such as hemoglobin digestion, erythrocyte invasion, parasite growth and parasite escape from the host cell. It is a valid target to develop antimalarial drugs. In the present work, we employed 3D QSAR modeling, pharmacophore modeling, and molecular docking to identify novel potent inhibitors that bind with M18AAP of P. falciparum. RESULTS The PLSR QSAR model showed highest value for correlation coefficient r(2) (88 %) and predictive correlation coefficient (pred_r2) =0.6101 for external test set among all QSAR models. The pharmacophore modeling identified DHRR (one hydrogen donor, one hydrophobic group, and two aromatic rings) as an essential feature of PfM18AAP inhibitors. The combined approach of 3D QSAR, pharmacophore, and structure-based molecular docking yielded 10 novel PfM18AAP inhibitors from ChEMBL antimalarial library, 2 novel inhibitors from each derivative of quinine, chloroquine, 8-aminoquinoline and 10 novel inhibitors from WHO antimalarial drugs. Additionally, high throughput virtual screening identified top 10 compounds as antimalarial leads showing G-scores -12.50 to -10.45 (in kcal/mol), compared with control compounds(G-scores -7.80 to -4.70) which are known antimalarial M18AAP inhibitors (AID743024). This result indicates these novel compounds have the best binding affinity for PfM18AAP. CONCLUSION The 3D QSAR models of PfM18AAP inhibitors provided useful information about the structural characteristics of inhibitors which are contributors of the inhibitory potency. Interestingly, In this studies, we extrapolate that the derivatives of quinine, chloroquine, and 8-aminoquinoline, for which there is no specific target has been identified till date, might show the antimalarial effect by interacting with PfM18AAP.

中文翻译：

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恶性疟原虫M18天冬氨酰氨肽酶的3D QSAR，药效基团和分子对接研究以及新型抑制剂的设计。

背景技术恶性疟原虫M18天冬氨酰氨肽酶（PfM18AAP）仅是在恶性疟原虫基因组中发现的天冬氨酰氨肽酶，并且对于其存活是必不可少的。PfM18AAP酶在寄生虫和红细胞宿主中执行各种功能，例如血红蛋白消化，红细胞入侵，寄生虫生长和寄生虫从宿主细胞逃逸。开发抗疟药是一个有效的目标。在目前的工作中，我们采用了3D QSAR建模，药效团建模和分子对接技术，以鉴定与恶性疟原虫M18AAP结合的新型有效抑制剂。结果在所有QSAR模型中，PLSR QSAR模型的相关系数r（2）最高（88％），而外部测试集的预测相关系数（pred_r2）= 0.6101。药效团模型确定DHRR（一个氢供体，一个疏水基和两个芳香环）是PfM18AAP抑制剂的基本特征。3D QSAR，药效基团和基于结构的分子对接相结合的方法从ChEMBL抗疟文库中获得了10种新颖的PfM18AAP抑制剂，从奎宁，氯喹，8-氨基喹啉的每种衍生物中获得了2种新颖的抑制剂，并从WHO的抗疟药中获得了10种新颖的抑制剂。此外，与已知的抗疟疾M18AAP抑制剂的对照化合物（G分数-7.80至-4.70）相比，高通量虚拟筛选将前10种化合物确定为抗疟疾线索，显示G分数为-12.50至-10.45（以kcal / mol计）（ AID743024）。该结果表明这些新型化合物对PfM18AAP具有最佳结合亲和力。结论PfM18AAP抑制剂的3D QSAR模型提供了有关抑制剂结构特征的有用信息，这些抑制剂是抑制能力的贡献者。有趣的是，在这项研究中，我们推断直到目前尚未确定针对其的特异性靶标的奎宁，氯喹和8-氨基喹啉衍生物可能通过与PfM18AAP相互作用而显示出抗疟作用。