Rational design and evaluation of new lead compound structures for selective betaARK1 inhibitors

J Med Chem. 2002 May 23;45(11):2150-9. doi: 10.1021/jm010093a.

Abstract

Beta-adrenergic receptor kinase 1 (betaARK1) and cyclic adenosine 5'-monophosphate-dependent protein kinase A (PKA) have structurally similar adenine-binding pockets but have different physiologic functions. To obtain specific betaARK1 inhibitors, a two step rational drug design process was used. First, a search was conducted on three-dimensional models of commercially available compounds to find compounds that fit the adenine-binding pocket of betaARK1. Second, a comparative docking study that focused on the differences between the adenine-binding pockets of the two enzymes was used to evaluate the binding specificity of each compound that inhibited betaARK1 activity. The results of these analyses yielded three betaARK1-selective inhibitor leads from 11 candidates, a hit rate for selectivity of 27%. Although the IC50 values of these compounds for betaARK1 ranged from only 1.3 x 10(-4) M to 5.6 x 10(-4) M, the compounds did not inhibit PKA at concentrations up to 1.0 x 10(-3) M. Thus, the present study shows the usefulness of a rational drug design strategy in finding specific kinase inhibitors for proteins with similar drug target binding sites.

MeSH terms

  • Binding Sites
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*
  • Cyclic AMP-Dependent Protein Kinases / chemistry
  • Databases, Factual
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Models, Molecular
  • Protein Conformation
  • Structure-Activity Relationship
  • beta-Adrenergic Receptor Kinases

Substances

  • Enzyme Inhibitors
  • Cyclic AMP-Dependent Protein Kinases
  • beta-Adrenergic Receptor Kinases