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Development of a pharmacorphore model for pharmacological chaperones targeting mutant trafficking-deficient CNG channels
Journal of Cheminformatics volume 5, Article number: O18 (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 .
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 . With this data we created several pharmacophore models using Schrödinger Phase , 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.
Our in-house database TueScreen, which includes ZINC12 , 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.
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.
Taeger , et al: unpublished data
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.
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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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
- Signal Transduction
- Active Compound
- Missense Mutation
- Chemical Feature
- Experimental Activity