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

Céline Simonin1, Mahendra Awale1, Michael Brand1

  • 1Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR TransCure, University of Bern, Freiestrasse 3, 3012 Bern (Switzerland).

Angewandte Chemie (International Ed. in English)
|October 13, 2015
PubMed

Insights

Researchers discovered the first potent TRPV6 inhibitor, a calcium channel linked to breast and prostate cancers. This novel compound, identified using the xLOS computational method, effectively blocks TRPV6-mediated calcium influx, impacting cancer cell growth.

Area of Science:

  • Medicinal Chemistry
  • Computational Chemistry
  • Oncology

Background:

  • Transient Receptor Potential Vanilloid 6 (TRPV6) is a calcium channel implicated in breast and prostate cancer.
  • Overexpression of TRPV6 contributes to cancer progression by regulating calcium influx.
  • Targeting TRPV6 presents a potential therapeutic strategy for these cancers.

Purpose of the Study:

  • To discover and characterize the first potent and selective inhibitor of TRPV6.
  • To utilize the inhibitor to investigate the effects of blocking TRPV6-mediated calcium influx on cancer cell growth.
  • To demonstrate the utility of the xLOS computational method for drug discovery.

Main Methods:

  • Ligand-based virtual screening (LBVS) using the xLOS 3D-shape and pharmacophore similarity algorithm.
  • Iterative rounds of virtual screening followed by chemical synthesis and optimization.
  • In vitro assays to determine inhibitor potency and selectivity against TRPV6.

Main Results:

  • Discovery of a novel, potent, and selective TRPV6 inhibitor with 0.3 μM inhibition.
  • The inhibitor effectively blocks TRPV6-mediated calcium influx.
  • The xLOS method successfully identified diverse chemical scaffolds crucial for inhibitor development.

Conclusions:

  • The developed TRPV6 inhibitor serves as a valuable tool compound for studying TRPV6 function in cancer.
  • The xLOS computational approach is effective for discovering inhibitors for poorly characterized targets.
  • Targeting TRPV6-mediated calcium influx holds promise for cancer therapy development.
Keywords:
TRP channelscalcium channelsdrug discoveryvirtual screening

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