Structure-based drug design using GPCR homology modeling: Toward the discovery of novel selective CysLT2 antagonists

3D structure of CysLT2 receptor was constructed by using homology modeling and molecular simulations. The binding pocket of CysLT2 receptor and the proposition of the interaction mode between CysLT2 and HAMI3379 were identified. A series of dicarboxylated chalcones was then virtually evaluated through molecular docking studies. A total of six compounds 13a–f with preferable scores was further synthesized and tested for CysLT2 antagonistic activities by determination of the cytosolic free Ca2+ levels in HEK293 cells. Compounds 13e and 13f exhibited potent and selective CysLT2 antagonistic activities with IC50 values being 7.5 and 0.25 μM, respectively.

Graphical abstract3D structure of CysLT2 was constructed and applied in the development of dicarboxylated chalcones as novel CysLT2 antagonists. 13e and 13f were identified as potent and selective CysLT2 antagonists.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 3D structure of CysLT2 receptor was firstly constructed. ► The interaction mode proposed would be useful and valuable. ► A total of six compounds was designed, synthesized and biological evaluated. ► Dicarboxylated chalcone is novel skeleton with CysLT2 antagonistic activities.