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Structure-Based Design and Synthesis of Benzothiazole Phosphonate Analogues with Inhibitors of Human ABAD-Aβ for Treatment of Alzheimer’s disease
Valasani, Koteswara Rao
Valasani, Koteswara Rao
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Abstract
Amyloid binding alcohol dehydrogenase (ABAD), a mitochondrial protein, is a cofactor facilitating amyloid-β peptide (Aβ) induced cell stress. Antagonizing Aβ-ABAD interaction protects against aberrant mitochondrial and neuronal function and improves learning memory in the Alzheimer’s disease (AD) mouse model. Therefore, it offers a potential target for Alzheimer’s drug design, by identifying potential inhibitors of Aβ-ABAD interaction. 2D QSAR methods were applied to novel compounds with known IC50 values, which formed a training set. A correlation analysis was carried out comparing the statistics of the measured IC50 with predicted values. These selectivity-determining descriptors were interpreted graphically in terms of principle component analyses, which are highly informative for the lead optimization process with respect to activity enhancement. A 3D pharmacophore model also was created. The 2D QSAR and 3D pharmacophore models will assist in hi-throughput screening. In addition, ADME descriptors were also determined to study their pharmacokinetic properties. Finally, ABAD molecular docking study of these novel molecules was undertaken to determine whether these compounds exhibit significant binding affinity with the binding site. We have synthesized only the compounds that have shown the best drug like properties as candidates for further studies.
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This is the peer reviewed version of the following article: Valasani, K. R., Hu, G., Chaney, M. O. and Yan, S. S. (2013), Structure-Based Design and Synthesis of Benzothiazole Phosphonate Analogues with Inhibitors of Human ABAD-Aβ for Treatment of Alzheimer’s Disease. Chemical Biology & Drug Design, 81: 238–249. doi:10.1111/cbdd.12068, which has been published in final form at http://doi.org/10.1111/cbdd.12068. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Date
2013-02
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Wiley
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Valasani_2013.pdf
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Molecular Docking, Quantitative Structure Activity Relationship, ADME Prediction, ABAD Inhibitors, Benzothiazole Aminophosphonates
Citation
Valasani, K. R., Hu, G., Chaney, M. O. and Yan, S. S. (2013), Structure-Based Design and Synthesis of Benzothiazole Phosphonate Analogues with Inhibitors of Human ABAD-Aβ for Treatment of Alzheimer’s Disease. Chemical Biology & Drug Design, 81: 238–249. doi:10.1111/cbdd.12068