TY - JOUR
T1 - Optimization of TRPV6 calcium channel inhibitors using a 3D ligand-based virtual screening method
AU - Simonin, Céline
AU - Awale, Mahendra
AU - Brand, Michael
AU - Van Deursen, Ruud
AU - Schwartz, Julian
AU - Fine, Michael
AU - Kovacs, Gergely
AU - Häfliger, Pascal
AU - Gyimesi, Gergely
AU - Sithampari, Abilashan
AU - Charles, Roch Philippe
AU - Hediger, Matthias A.
AU - Reymond, Jean Louis
N1 - Publisher Copyright:
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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 μM 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. A pharmacophore similarity algorithm called xLOS was used in combination with chemical synthesis to entirely change the scaffold of a weak, unselective inhibitor of calcium channel TRPV6 to obtain a potent, selective inhibitor. Inhibition of TRPV6 selectively reduced cancer cell growth. This virtual screening method may be generally useful to develop tool compounds for poorly characterized targets.
AB - 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 μM 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. A pharmacophore similarity algorithm called xLOS was used in combination with chemical synthesis to entirely change the scaffold of a weak, unselective inhibitor of calcium channel TRPV6 to obtain a potent, selective inhibitor. Inhibition of TRPV6 selectively reduced cancer cell growth. This virtual screening method may be generally useful to develop tool compounds for poorly characterized targets.
KW - TRP channels
KW - calcium channels
KW - drug discovery
KW - virtual screening
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U2 - 10.1002/anie.201507320
DO - 10.1002/anie.201507320
M3 - Article
C2 - 26457814
AN - SCOPUS:84983166376
SN - 1433-7851
VL - 54
SP - 14748
EP - 14752
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 49
ER -