Rational Design and Evaluation of New Lead Compound Structures for Selective βARK1 Inhibitors

β-Adrenergic receptor kinase 1 (βARK1) and cyclic adenosine 5‘-monophosphate-dependent protein kinase A (PKA) have structurally similar adenine-binding pockets but have different physiologic functions. To obtain specific βARK1 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 βARK1. 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 βARK1 activity. The results of these analyses yielded three βARK1-selective inhibitor leads from 11 candidates, a hit rate for selectivity of 27%. Although the IC50 values of these compounds for βARK1 ranged from only 1.3 × 10-4 M to 5.6 × 10-4 M, the compounds did not inhibit PKA at concentrations up to 1.0 × 10-3 M. Thus, the present study shows the usefulness of a rat...