25-30 August 2019
Henry Ford Building
Europe/Berlin timezone

Structure Based Design of A$\beta$(1-42) Small Molecule Reporters

Not scheduled
Harnack House and Henry Ford Building

Harnack House and Henry Ford Building

Board: 212
Poster Posters


Ms Janina Kaderli (Department of Chemistry and Applied Biosciences (D-CHAB), ETH Zurich)


An important pathological hallmark of aggregation related neurodegenerative diseases, such as Alzheimer's or Parkinson's disease, is the formation of highly ordered cross-$\beta$-sheet containing structures, termed amyloids.$^{1,2}$ Taking advantage of these, non-invasive positron emission tomography (PET) in combination with 3D-imaging techniques offers a promising approach for early stage diagnosis. However, detecting the distribution of tracer molecules in the brain, PET is strongly limited by pharmacokinetics and binding selectivity of the applied ligands. Structure based in silico screening offers a fast and simple strategy to identify new possible tracer molecules. We generated a pharmacophore model based on the surface properties of the A$\beta$(1-42) structure (PDB code 2nao).$^{3}$ Molecule supplier database screening, followed by additional molecule property related selection, lead to a reasonable small set of molecules exhibiting the ability to bind into the chosen binding pocket. We validated molecular fragment hits in vitro for protein interaction, as well as binding selectivity, using STD NMR and HPLC. Following this approach, we were able to identify several new potential tracer molecules showing good A$\beta$(1-42) selectivity, as well as binding affinities in the micromolar range. Overall, the in silico structure based molecule screening in combination with in vitro analysis is a time and sample efficient method allowing for more profound ligand investigation.

  1. Sunde, M.; Serpell, L. C.; Bartlam, M.; Fraser, P. E.; Pepys, M. B.; Blake, C. C. F.: Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J. Mol. Biol. 1997, 273, 729-739.
  2. Ross, C. A.; Poirier, M. A.: Protein aggregation and neurodegenerative disease. Nat. Med. 2004, 10, S10-S17.
  3. Wälti, M. A.; Ravotti, F.; Arai, H.; Glabe, C. G.; Wall, J. S.; Böckmann, A.; Güntert, P.; Meier, B. H.; Riek, R.: Atomic-resolution structure of a disease-relevant A$\beta$(1-42) amyloid fibril. Proc. Natl. Acad. Sci. USA 2016, 113, E4976-E4984.

Primary authors

Ms Janina Kaderli (Department of Chemistry and Applied Biosciences (D-CHAB), ETH Zurich) Dr Dhiman Ghosh (Department of Chemistry and Applied Biosciences (D-CHAB), ETH Zurich) Prof. Roland Riek (Department of Chemistry and Applied Biosciences (D-CHAB), ETH Zurich) Dr Julien Orts (Department of Chemistry and Applied Biosciences (D-CHAB), ETH Zurich)

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