In silico analysis on hERG channel blocking effect of a series of T-type calcium channel blockers

Title
In silico analysis on hERG channel blocking effect of a series of T-type calcium channel blockers
Authors
장재완송치만최기현조용서백두종신계정배애님
Keywords
hERG; T-type calcium channel blockers; CoMSIA
Issue Date
2011-01
Publisher
Bulletin of the Korean Chemical Society
Citation
VOL 32, NO 1, 251-262
Abstract
Human ether-a-go-go related gene (hERG) potassium channel blockade, an undesirable side effect which might cause sudden cardiac death, is one of the major concerns facing the pharmaceutical industry. The purpose of this study is to develop an in silico QSAR model which uncovers the structural parameters of T-type calcium channel blockers to reduce hERG blockade. Comparative molecular similarity indices analysis (CoMSIA) was conducted on a series of piperazine and benzimidazole derivatives bearing methyl 5-(ethyl(methyl)amino)-2-isopropyl-2-phenylpentanoate moieties, which was synthesized by our group. Three different alignment methods were applied to obtain a reliable model: ligand based alignment, pharmacophore based alignment, and receptor guided alignment. The CoMSIA model with receptor guided alignment yielded the best results : r2 = 0.955, q2 = 0.781, r2pred = 0.758. The generated CoMSIA contour maps using electrostatic, hydrophobic, H-bond donor, and acceptor fields explain well the structural requirements for hERG nonblockers and also correlate with the lipophilic potential map of the hERG channel pore.
URI
http://pubs.kist.re.kr/handle/201004/41036
ISSN
0253-2964
Appears in Collections:
KIST Publication > Article
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