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

J Med Chem. 2006 Jan 26;49(2):501-10. doi: 10.1021/jm0503751.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

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