Structure-Based Drug Designing Recommends HDAC6 Inhibitors To Attenuate Microtubule-Associated Tau-Pathogenesis

Published on Mar 20, 2019in Analytical Chemistry6.35
· DOI :10.1021/acschemneuro.8b00405
Amir Zeb5
Estimated H-index: 5
(Gyeongsang National University),
Chanin Park8
Estimated H-index: 8
(Gyeongsang National University)
+ 3 AuthorsKeun Woo Lee30
Estimated H-index: 30
(Gyeongsang National University)
Protein acetylation and deacetylation play vital roles in the structural and physiological behavior of target proteins. Histone deacetylase 6 (HDAC6) remains a key therapeutic target in several chronic diseases such as cancer, neurodegenerative, and hematological diseases. In tau-pathogenesis, HDAC6 tightly regulates microtubule-associated tau physiology, and its inhibition suppresses Alzheimer’s phenotype. To this end, the current study has identified novel HDAC6 inhibitors by structure-based drug designing method. A pharmacophore was generated from HDAC6 in complex with trichostatin A. The selected pharmacophore had five features including two hydrogen bond donors, one hydrogen bond acceptor, and two hydrophobic features. Pharmacophore validation obtained the highest GH score of 0.80. By applying Lipinski’s rule of five and ADMET Descriptors, a drug-like database of 29 183 molecules was generated from the Zinc Natural Product Database. The validated pharmacophore screened 841 drug-like molecules and was...
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