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J Med Chem. 2006 Jan 26;49(2):501-10.

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

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School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland.


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.

[Indexed for MEDLINE]

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