Homology modeling and atomic level binding study of GABA(A) 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 alpha1beta2gamma2 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 alpha 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.
Cheng
Jin
J
Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan 430073, PR China.
Ju
Xiu-Lian
XL
D000577:Amides / Q000737:chemistry* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D014101:Torpedo
C428944:AChBP protein, Lymnaea; D000577:Amides; D002352:Carrier Proteins; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic