Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand‐Based Virtual Screening Method. Issue 49 (12th October 2015)

• Record Type: Journal Article
• Authors: Simonin, Céline; Awale, Mahendra; Brand, Michael; van Deursen, Ruud; Schwartz, Julian; Fine, Michael; Kovacs, Gergely; Häfliger, Pascal; Gyimesi, Gergely; Sithampari, Abilashan; Charles, Roch‐Philippe; Hediger, Matthias A.; Reymond, Jean‐Louis
• Is Part Of: Angewandte Chemie international edition. Volume 54:Issue 49(2015)
• Page Start: 14748
• Page End: 14752
• Publication Date: 2015-10-12
• Subjects: calcium channels -- drug discovery -- TRP channels -- virtual screening; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201507320
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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 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. Abstract : 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.