Homology modeling and atomic level binding study of GABAA receptor with novel enaminone amides

A series of novel enaminone amides with improved side effect were synthesized by Hogenkamp et al. To explore the action mechanisms of enaminone amides, the homology model of rat α1β2γ2 GABAR was generated using the cryo-electron microscopy structure of the nAChR of Torpedo marmorata and the AChBP of Lymnaea stagnalis as the templates. Molecular docking and pharmacophore analyses allowed us to speculate the critical residues involving to the recognition of the ligands. The docking results indicated His128, Tyr186 and Tyr236 of α subunit were essential to form H-bond interactions contacts with the ligands. Specially, the N-substituents of enaminone amides as the sterically favored areas could form the important hydrophobic interactions with the residue Tyr186.

Graphical abstractThe binding modes of novel enaminone amides with rat α1β2γ2 GABAR were studies by molecular docking and pharmacophore analyses. The results indicate His128, Tyr186 and Tyr236 of α subunit of GABAR are essential to form protein–ligand interactions.Figure optionsDownload full-size imageDownload as PowerPoint slide