Pharmacophore modeling of human adenosine receptor A(₂A) antagonists

J Mol Model. 2010 Dec;16(12):1867-76. doi: 10.1007/s00894-010-0690-z. Epub 2010 Mar 12.

Abstract

Three-dimensional pharmacophore models of human adenosine receptor A(₂A) antagonists were developed based on 23 diverse compounds selected from a large number of A(₂A) antagonists. The best pharmacophore model, Hypo1, contained five features: one hydrogen bond donor , three hydrophobic points and one ring aromatic. Its correlation coefficient, root mean square deviation, and cost difference values were 0.955, 0.921 and 84.4, respectively, suggested that the Hypo1 model was reasonable and reliable. This model was validated by three methods: a test set of 106 diverse compounds, a simulated virtual screening, and superimposition with the crystal structure of A(₂A) receptor. The results showed that Hypo1 was not only in agreement with the A(₂A) crystal structure and literature reports, but also well identified active A(₂A) antagonists from the virtual database. This methodology provides helpful information and a robust tool for the discovery of potent A(₂A) antagonists.

MeSH terms

  • Adenosine A2 Receptor Antagonists / chemistry*
  • Adenosine A2 Receptor Antagonists / metabolism
  • Adenosine A2 Receptor Antagonists / pharmacology
  • Algorithms
  • Binding Sites
  • Catalytic Domain
  • Computer Simulation
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Models, Chemical
  • Models, Molecular*
  • Molecular Structure
  • Receptors, Adenosine A2 / chemistry*
  • Structure-Activity Relationship

Substances

  • Adenosine A2 Receptor Antagonists
  • Receptors, Adenosine A2