Computational study of antagonist/alpha1A adrenoceptor complexes--observations of conformational variations on the formation of ligand/receptor complexes.

Abstract

As selective antagonist inhibition may relieve the symptoms of benign prostatic hyperplasia, we have examined the interactions of antagonists including quinazoline and imidazolidinium/guanidinium compounds complexed with a homology model of the alpha(1A) adrenoceptor. Our approach involves docking of ligands of various structural classes followed by molecular dynamics simulations of antagonist/receptor complexes, which demonstrates that different structural classes of antagonist induce different receptor conformations upon binding with particular variations noted in the conformation of TM-V. Subsequently, we examined the interactions and the conformational flexibility of alpha(1) and alpha(1A) adrenoceptor antagonists, with the ligand-induced receptor conformers. This study indicated that a receptor conformation induced by one structural class of antagonist is not suitable for direct screening of another class. Our analysis indicates that computational high-throughput screening is likely to give inaccurate data on binding and selectivity and such studies need to consider conformational changes in the receptor.

• Authors: Gemma K Kinsella, Isabel Rozas, Graeme W Watson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 2 Pg. 501-10 (Jan 26 2006) ISSN: 0022-2623 [Print] United States
• PMID: 16420037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-1 Receptor Antagonists
• Adrenergic alpha-Antagonists
• Ligands
• Receptors, Adrenergic, alpha-1

Topics

• Adrenergic alpha-1 Receptor Antagonists
• Adrenergic alpha-Antagonists (chemistry)
• Binding Sites
• Ligands
• Models, Molecular
• Molecular Conformation
• Quantitative Structure-Activity Relationship
• Receptors, Adrenergic, alpha-1 (chemistry)