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

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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
figure1

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.

References

  1. 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.

  2. 2.

    Taeger , et al: unpublished data

  3. 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.

  4. 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.

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Author information

Correspondence to Charlotta PI Schärfe.

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

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Schärfe, C.P., Taeger, J., Reuter, P. et al. Development of a pharmacorphore model for pharmacological chaperones targeting mutant trafficking-deficient CNG channels. J Cheminform 5, O18 (2013) doi:10.1186/1758-2946-5-S1-O18

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Keywords

  • Signal Transduction
  • Active Compound
  • Missense Mutation
  • Chemical Feature
  • Experimental Activity