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Computational study of antagonist/α1A-adrenoceptor complexes: Observation of conformational variation on the formation of ligand/receptor complexes
J. Med. Chem. (2006)
  • Gemma K Kinsella, Dr
  • Isabel Rozas, Prof
  • Graeme Watson, Prof
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 α1A 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 α1 and α1A 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.

Publication Date
2006
Citation Information
Gemma K Kinsella, Isabel Rozas and Graeme Watson. "Computational study of antagonist/α1A-adrenoceptor complexes: Observation of conformational variation on the formation of ligand/receptor complexes" J. Med. Chem. Vol. 49 Iss. 2 (2006)
Available at: http://works.bepress.com/gemma_kinsella/18/