Volume 5 Supplement 1

8th German Conference on Chemoinformatics: 26 CIC-Workshop

Open Access

Development of a pharmacorphore model for pharmacological chaperones targeting mutant trafficking-deficient CNG channels

  • Charlotta PI Schärfe1Email author,
  • Joachim Taeger2,
  • Peggy Reuter2,
  • Nina M Fischer1,
  • Jens Krüger1,
  • Bernd Wissinger2 and
  • Oliver Kohlbacher1
Journal of Cheminformatics20135(Suppl 1):O18

DOI: 10.1186/1758-2946-5-S1-O18

Published: 22 March 2013

Complete colorblindness (achromatopsia) is caused by autosomal recessively inherited mutations in the retinal phototransduction pathway, predominantly in the CNGA3- and CNGB3-subunit of the cyclic nucleotide-gated (CNG) channels in cone photoreceptors. CNGA3, which is mutated in about 25% of the achromatopsia patients, mainly harbors missense mutations which frequently impair the folding and/or trafficking of the mutant CNGA3-channels [1].

Pharmacological chaperones stabilizing the folding of the mutant protein may be used to overcome this folding-/trafficking-deficiency. More than 50 compounds were evaluated in their ability to restore signal transduction using a calcium imaging-based bioassay utilizing the CNGA3-mutant E228K [2]. With this data we created several pharmacophore models using Schrödinger Phase [3], which describe the chemical features of potential pharmacological chaperones targeting achromatopsia.

We used several approaches leading to different pharmacophore hypotheses:

a) Training with the complete set of experimental data (see Figure 1)

b) Training with only dihydropyridines since this group showed the highest experimental activity, and

c) Training with a data set excluding dihydropyridines.
Figure 1

Pharmacophore depicting potential features of CNG channel-chaperones.

Our in-house database TueScreen, which includes ZINC12 [4], was screened to identify potentially active compounds. As a result, several potential molecule classes could be found that may be useful as pharmacological chaperones to improve folding/trafficking of mutant CNG-channels. We will experimentally validate these predictions in a calcium imaging-based bioassay.

Authors’ Affiliations

(1)
Applied Bioinformatics, Center for Bioinformatics, Quantitative Biology Center and Department of Computer Science, University of Tübingen
(2)
Molecular Genetics Laboratory, Institute for Ophthalmic Research, Center for Ophthalmology

References

  1. Reuter P, et al: Mutations in CNGA3 Impair Trafficking or Function of Cone Cyclic Nucleotide-Gated Channels, Resulting in Achromatopsia. Human Mutation. 2008, 29: 1228-1236. 10.1002/humu.20790.View ArticleGoogle Scholar
  2. Taeger , et al: unpublished dataGoogle Scholar
  3. Dixon SL, et al: PHASE: A Novel Approach to Pharmacophore Modeling and 3D Database Searching. Chem Biol Drug Des. 2006, 67: 370-372. 10.1111/j.1747-0285.2006.00384.x.View ArticleGoogle Scholar
  4. Irwin JJ, et al: ZINC: A Free Tool to Discover Chemistry for Biology. J Chem Inf Model. 2012, 52: 1757-1768. 10.1021/ci3001277.View ArticleGoogle Scholar

Copyright

© Schärfe et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.