Optimization of TRPV6 calcium channel inhibitors using a 3D ligand-based virtual screening method

Céline Simonin, Mahendra Awale, Michael Brand, Ruud Van Deursen, Julian Schwartz, Michael Fine, Gergely Kovacs, Pascal Häfliger, Gergely Gyimesi, Abilashan Sithampari, Roch Philippe Charles, Matthias A. Hediger, Jean Louis Reymond

Research output: Contribution to journalArticle

19 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)14748-14752
Number of pages5
JournalAngewandte Chemie - International Edition
Volume54
Issue number49
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Calcium Channels
Calcium
Screening
Ligands
Cell growth
Scaffolds
Molecules
Computational methods
Seed

Keywords

  • calcium channels
  • drug discovery
  • TRP channels
  • virtual screening

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

Cite this

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 A.; Reymond, Jean Louis.

In: Angewandte Chemie - International Edition, Vol. 54, No. 49, 01.01.2015, p. 14748-14752.

Research output: Contribution to journalArticle

Simonin, C, Awale, M, Brand, M, Van Deursen, R, Schwartz, J, Fine, M, Kovacs, G, Häfliger, P, Gyimesi, G, Sithampari, A, Charles, RP, Hediger, MA & Reymond, JL 2015, 'Optimization of TRPV6 calcium channel inhibitors using a 3D ligand-based virtual screening method', Angewandte Chemie - International Edition, vol. 54, no. 49, pp. 14748-14752. https://doi.org/10.1002/anie.201507320
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. / Optimization of TRPV6 calcium channel inhibitors using a 3D ligand-based virtual screening method. In: Angewandte Chemie - International Edition. 2015 ; Vol. 54, No. 49. pp. 14748-14752.
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