Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand‐Based Virtual Screening Method |
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| Authors: | Dr. Céline Simonin Dr. Mahendra Awale Michael Brand Dr. Ruud van Deursen Dr. Julian Schwartz Dr. Michael Fine Dr. Gergely Kovacs Pascal Häfliger Dr. Gergely Gyimesi Abilashan Sithampari Prof. Dr. Roch‐Philippe Charles Prof. Dr. Matthias A. Hediger Prof. Dr. Jean‐Louis Reymond |
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| Affiliation: | 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) |
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| 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 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. |
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| Keywords: | calcium channels drug discovery TRP channels virtual screening |
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