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

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; Reymond, Jean-Louis (2015). Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method. Angewandte Chemie (International ed.), 54(49), pp. 14748-14752. Wiley-VCH 10.1002/anie.201507320

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Service Sector > Institute of Pathology
08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Simonin, Céline; Awale, Mahendra; van Deursen, Ruud; Schwartz, Julian; Fine, Michael; Häfliger, Pascal; Gyimesi, Gergely; Sithampari, Abilashan; Charles, Roch-Philippe; Hediger, Matthias and Reymond, Jean-Louis

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
500 Science > 540 Chemistry

ISSN:

1433-7851

Publisher:

Wiley-VCH

Language:

English

Submitter:

Sandra Tanja Zbinden Di Biase

Date Deposited:

22 Jan 2016 14:02

Last Modified:

16 Feb 2018 10:07

Publisher DOI:

10.1002/anie.201507320

PubMed ID:

26457814

BORIS DOI:

10.7892/boris.74706

URI:

https://boris.unibe.ch/id/eprint/74706

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