Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain.
School of Biosciences, University of Kent, Canterbury, Kent, CT2 7NJ, UK.
Future Med Chem. 2019 Jul;11(14):1703-1720. doi: 10.4155/fmc-2018-0592. Epub 2019 Aug 2.
Due to the urgent need for effective drugs to treat schistosomiasis that act through a known molecular mechanism of action, we focused on a target-based approach with the aim to discover inhibitors of a cyclic nucleotide phosphodiesterase from (SmPDE4A). To discover new inhibitors of SmPDE4A homology models of the enzyme structure were constructed based on known human and protozoan homologs. The best two models were selected for subsequent virtual screening of our in-house chemical library. A total of 25 library compounds were selected for experimental confirmation as SmPDE4A inhibitors and after dose-response experiments, three top hits were identified. The results presented validate the virtual screening approach to identify new inhibitors for clinically relevant phosphodiesterases.
由于迫切需要通过已知作用机制的有效药物来治疗血吸虫病，我们专注于基于靶点的方法，旨在发现来自（Schistosoma mansoni）的环核苷酸磷酸二酯酶抑制剂（SmPDE4A）。为了发现 SmPDE4A 的新抑制剂，我们根据已知的人类和原生动物同源物构建了该酶结构的同源模型。选择了两个最佳模型用于随后对我们内部化学文库进行虚拟筛选。共有 25 种文库化合物被选为 SmPDE4A 抑制剂的实验验证，经过剂量反应实验，鉴定出了三个最佳抑制剂。所呈现的结果验证了用于鉴定临床相关磷酸二酯酶的新型抑制剂的虚拟筛选方法。
