Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method

被引：45

作者：

Simonin, Celine ^{[1
]}

Awale, Mahendra ^{[1
]}

Brand, Michael ^{[1
]}

van Deursen, Ruud ^{[1
]}

Schwartz, Julian ^{[1
]}

Fine, Michael ^{[2
]}

Kovacs, Gergely ^{[2
]}

Haefliger, Pascal ^{[2
]}

Gyimesi, Gergely ^{[2
]}

Sithampari, Abilashan ^{[2
]}

Charles, Roch-Philippe ^{[2
]}

Hediger, Matthias A. ^{[2
]}

Reymond, Jean-Louis ^{[1
]}

机构：

[1] Univ Bern, Dept Chem & Biochem, Natl Ctr Competence Res NCCR TransCure, CH-3012 Bern, Switzerland

[2] Univ Bern, Inst Biochem & Mol Med, Natl Ctr Competence Res NCCR TransCure, CH-3012 Bern, Switzerland

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2015年 / 54卷 / 49期

基金：

瑞士国家科学基金会;

关键词：

calcium channels; drug discovery; TRP channels; virtual screening; ZINC; BIOLOGY;

D O I：

10.1002/anie.201507320

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Herein, we report the discovery of the first potent and selective inhibitor of TRPV6, a calcium channel overexpressed in breast and prostate cancer, and its use to test the effect of blocking TRPV6-mediated Ca2+-influx on cell growth. The inhibitor was discovered through a computational method, xLOS, a 3D-shape and pharmacophore similarity algorithm, a type of ligand-based virtual screening (LBVS) method described briefly here. Starting with a single weakly active seed molecule, two successive rounds of LBVS followed by optimization by chemical synthesis led to a selective molecule with 0.3 mm inhibition of TRPV6. The ability of xLOS to identify different scaffolds early in LBVS was essential to success. The xLOS method may be generally useful to develop tool compounds for poorly characterized targets.

引用

页码：14748 / 14752

页数：5

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