Rational design and evaluation of new lead compound structures for selective betaARK1 inhibitors.
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.
Iino
Minoru
M
Discovery Research Laboratories and New Product Research Laboratories II, Tokyo R&D Center, Daiichi Pharmaceutical Co., Ltd., 16-13 Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan.
Furugori
Taketoshi
T
Mori
Tomohiro
T
Moriyama
Sachiko
S
Fukuzawa
Akiko
A
Shibano
Toshiro
T
D001665:Binding Sites; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D051552:beta-Adrenergic Receptor Kinases
D004791:Enzyme Inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases