title: Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method.
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.
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012 Bern (Switzerland).
authors.forename: Céline
authors.initials: C
authors.lastname: Simonin
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012 Bern (Switzerland).
authors.forename: Mahendra
authors.initials: M
authors.lastname: Awale
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012 Bern (Switzerland).
authors.forename: Michael
authors.initials: M
authors.lastname: Brand
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012 Bern (Switzerland).
authors.forename: Ruud
authors.initials: R
authors.lastname: van Deursen
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012 Bern (Switzerland).
authors.forename: Julian
authors.initials: J
authors.lastname: Schwartz
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3012 Bern (Switzerland).
authors.forename: Michael
authors.initials: M
authors.lastname: Fine
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3012 Bern (Switzerland).
authors.forename: Gergely
authors.initials: G
authors.lastname: Kovacs
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3012 Bern (Switzerland).
authors.forename: Pascal
authors.initials: P
authors.lastname: Häfliger
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3012 Bern (Switzerland).
authors.forename: Gergely
authors.initials: G
authors.lastname: Gyimesi
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3012 Bern (Switzerland).
authors.forename: Abilashan
authors.initials: A
authors.lastname: Sithampari
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3012 Bern (Switzerland).
authors.forename: Roch-Philippe
authors.initials: RP
authors.lastname: Charles
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCR TransCure, University of Bern, Bühlstrasse 28, 3012 Bern (Switzerland). matthias.hediger@ibmm.unibe.ch.
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Hediger
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012 Bern (Switzerland). jean-louis.reymond@dcb.unibe.ch.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Reymond
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D008024:Ligands; D050916:TRPV Cation Channels; C422827:TRPV6 protein, human
keywords: TRP channels; calcium channels; drug discovery; virtual screening