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Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand‐Based Virtual Screening Method
Author(s) -
Simonin Céline,
Awale Mahendra,
Brand Michael,
van Deursen Ruud,
Schwartz Julian,
Fine Michael,
Kovacs Gergely,
Häfliger Pascal,
Gyimesi Gergely,
Sithampari Abilashan,
Charles RochPhilippe,
Hediger Matthias A.,
Reymond JeanLouis
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201507320
Subject(s) - pharmacophore , virtual screening , ligand (biochemistry) , trpv6 , chemistry , calcium channel , calcium , biophysics , computational biology , stereochemistry , biochemistry , calcium metabolism , biology , receptor , organic chemistry
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 Ca 2+ ‐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 μ M 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.