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

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

  • Angew Chem Int Ed Engl. 2015 Dec 1;54(49):14748-52. doi: 10.1002/anie.201507320.
Céline Simonin 1,  Mahendra Awale 1,  Michael Brand 1,  Ruud van Deursen 1,  Julian Schwartz 1,  Michael Fine 2,  Gergely Kovacs 2,  Pascal Häfliger 2,  Gergely Gyimesi 2,  Abilashan Sithampari 2,  Roch-Philippe Charles 2,  Matthias A Hediger 3,  Jean-Louis Reymond 4
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012 Bern (Switzerland).
  • 2 Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3012 Bern (Switzerland).
  • 3 Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3012 Bern (Switzerland). [email protected].
  • 4 Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012 Bern (Switzerland). [email protected].
PMID: 26457814 DOI: 10.1002/anie.201507320
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.

Keywords

TRP channels; calcium channels; drug discovery; virtual screening.

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