Pharmacophore modeling of dual angiotensin II and endothelin A receptor antagonists.
Three-dimensional pharmacophore models were generated for AT1 and ET(A) receptors based on highly selective AT1 and ET(A) antagonists using the program Catalyst/HipHop. Both the best pharmacophore model for selective AT1 antagonists (Hypo-AT(1)-7) and ETA antagonists (Hypo-ET(A)-1) were obtained through a careful validation process. All five features contained in Hypo-AT(1)-7 and Hypo-ET(A)-1 (hydrogen-bond acceptor (A), hydrophobic aliphatic (Z), negative ionizable (N), ring aromatic (R), and hydrophobic aromatic (Y)) seem to be essential for antagonists in terms of binding activity. Dual AT1 and ET(A) receptor antagonists (DARAs) can map to both Hypo-AT(1)-7 and Hypo-ET(A)-1, separately. Comparison of Hypo-AT(1)-7 and Hypo-ET(A)-1, not only AT1 and ET(A) antagonist pharmacophore models consist of essential features necessary for compounds to be highly active and selective toward their corresponding receptor, but also have something in common. The results in this study will act as a valuable tool for designing and researching structural relationship of novel dual AT1 and ET(A) receptor antagonists.
Xue
Wei-Zhe
WZ
School of Chemical Engineering and the Environment, Beijing Institute of Technology, Beijing 100081, China.
Lü
Wei
W
Zhou
Zhi-Ming
ZM
Wang
Zhan-Li
ZL
D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry*; D015195:Drug Design; D065128:Endothelin Receptor Antagonists; D008958:Models, Molecular; D008968:Molecular Conformation
D047228:Angiotensin II Type 1 Receptor Blockers; D065128:Endothelin Receptor Antagonists