3D-QSAR Study of 1,4-Dihydropyridines Reveals Distinct Molecular Requirements of Their Binding Site in the Resting and the Inactivated State of Voltage-Gated Calcium Channels
Voltage-gated calcium channels (VGCC) are transmembrane proteins that mediate the calcium influx in response to membrane depolarization and thereby initiate cellular activities such as secretion, contraction, and gene expression. According to pharmacological and electrophysiological results they may be divided into the distinct L-, N-, P/Q-, R-, and T-type subfamilies. While all VGCC are composed of the pore-forming α1 subunits, the disulfide-linked α2δ subunits and the intracellular β subunits, only the skeletal muscle L-type channel has an additional transmembrane γ subunit. A second special feature of L-type channels is their unique reaction to the calcium entry blockers such as 1,4-dihydropyridines (DHP), phenylalkylamines and benzothiazepines that are therapeutically used against hypertension, angina pectoris and supraventricular arrhythmias, and the exceptional DHP channel activators (Bay k 8644, RS30026, CGP 28392 or Bay y 5959). However it is not the unique L-type γ subunit which is the physiological target of these compounds, but specific regions of the α1 subunit.
KeywordsEntropy Tyrosine Glycine Carboxylate Carbonyl
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