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Quantitative structure–activity relationship analysis of β-amyloid aggregation inhibitors

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Abstract

Inhibiting the aggregation process of the β-amyloid peptide is a promising strategy in treating Alzheimer’s disease. In this work, we have collected a dataset of 80 small molecules with known inhibition levels and utilized them to develop two comprehensive quantitative structure–activity relationship models: a Bayesian model and a decision tree model. These models have exhibited high predictive accuracy: 87% of the training and test sets using the Bayesian model and 89 and 93% of the training and test sets, respectively, by the decision tree model. Subsequently these models were used to predict the activities of several new potential β-amyloid aggregation inhibitors and these predictions were indeed validated by in vitro experiments. Key chemical features correlated with the inhibition ability were identified. These include the electro-topological state of carbonyl groups, AlogP and the number of hydrogen bond donor groups. The results demonstrate the feasibility of the developed models as tools for rapid screening, which could help in the design of novel potential drug candidates for Alzheimer’s disease.

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Acknowledgments

We thank Nir Ben-Tal and members of his laboratory for helpful discussions regarding the models and members of the Gazit laboratory for helpful discussions. The authors acknowledge the support of the DIP German-Israel Cooperation Program and the support of MERZ cooperation for this research.

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Authors and Affiliations

  1. Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978, Tel Aviv, Israel

    Shiri Stempler, Michal Levy-Sakin, Anat Frydman-Marom, Yaniv Amir, Roni Scherzer-Attali, Ludmila Buzhansky & Ehud Gazit

  2. Department of Chemistry, Bar-Ilan University, 52900, Ramat Gan, Israel

    Hanoch Senderowitz

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  1. Shiri Stempler
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  2. Michal Levy-Sakin
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  3. Anat Frydman-Marom
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  6. Ludmila Buzhansky
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Correspondence to Ehud Gazit or Hanoch Senderowitz.

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Stempler, S., Levy-Sakin, M., Frydman-Marom, A. et al. Quantitative structure–activity relationship analysis of β-amyloid aggregation inhibitors. J Comput Aided Mol Des 25, 135–144 (2011). https://doi.org/10.1007/s10822-010-9405-x

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