To discover drugs for toxoplasmosis with less side-effects and less probability to get drug resistance is eagerly appealed for pregnant women, infant or immunocompromised patients. In this work, using TgCDPK1 as drug target, we design a method to discover new inhibitors for CDPK1 as potential drug lead for toxoplasmosis with novel scaffolds based on the combination of 2D/3D-QSAR and scaffold-hopping methods. All the binding sites of the potential inhibitors were checked by docking method, and only the ones that docked to the most conserved sites of TgCDPK1, which make them have less probability to get drug resistance, were remained. As a result, 10 potential inhibitors within two new scaffolds were discovered for TgCDPK1 with experimentally verified inhibitory activities in micromole level. The discovery of these inhibitors may contribute to the drug development for toxoplasmosis. Besides, the pipeline which is composed in this work as the combination of QSAR and scaffold-hopping is simple, easy to repeat for researchers without need of in-depth knowledge of pharmacology to get inhibitors with novel scaffolds, which will accelerate the procedure of drug discovery and contribute to the drug repurposing study.

中文翻译：

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基于QSAR和支架跳跃法结合体外验证，发现具有新型支架的潜在弓形虫CDPK1抑制剂。

对于孕妇，婴儿或免疫功能低下的患者，急切地希望发现弓形虫病的药物副作用少，耐药性降低。在这项工作中，我们以TgCDPK1为药物靶标，结合2D / 3D-QSAR和支架跳跃方法，设计了一种方法，用新型支架发现CDPK1作为弓形虫病潜在药物的新抑制剂。通过对接方法检查了所有潜在抑制剂的结合位点，仅保留了与TgCDPK1最保守位点对接的那些位点，这些位点使它们获得耐药性的可能性较小。结果，在两个新支架中发现了10种潜在的TgCDPK1抑制剂，并在实验上证实了其在微摩尔水平上的抑制活性。这些抑制剂的发现可能有助于弓形虫病的药物开发。此外，这项工作由QSAR和支架跳跃相结合而构成的管道非常简单，对于研究人员而言无需重复药理即可轻松重复，而无需深入的药理学知识即可获得具有新型支架的抑制剂，这将加速药物的开发过程。发现并为药物再利用研究做出贡献。