In silico analysis on hERG channel blocking effect of a series of T-type calcium channel blockers
- In silico analysis on hERG channel blocking effect of a series of T-type calcium channel blockers
- 장재완; 송치만; 최기현; 조용서; 백두종; 신계정; 배애님
- hERG; T-type calcium channel blockers; CoMSIA
- Issue Date
- Bulletin of the Korean Chemical Society
- VOL 32, NO 1, 251-262
- 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.
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