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In silico Analysis on hERG Channel Blocking Effect of a Series of T-type Calcium Channel Blockers
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  • 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
저자명
Jang. Jae-Wan,Song. Chi-Man,Choi. Kee-Hyun,Cho. Yong-Seo,Baek. Du-Jong,Shin. Kye-Jung,Pae. Ae-Nim
간행물명
Bulletin of the Korean Chemical Society
권/호정보
2011년|32권 1호|pp.251-262 (12 pages)
발행정보
대한화학회
파일정보
정기간행물|ENG|
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기타
이 논문은 한국과학기술정보연구원과 논문 연계를 통해 무료로 제공되는 원문입니다.
서지반출

기타언어초록

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 : $r^2$ = 0.955, $q^2$ = 0.781, $r^2_{pred}$ = 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.