Combined ligand and fragment-based drug design of selective histone deacetylase – 6 inhibitors

Ruzic, Dusan, Petkovic, Milos, Agbaba, Danica, Ganesan, A. and Nikolic, Katarina (2019) Combined ligand and fragment-based drug design of selective histone deacetylase – 6 inhibitors. Molecular Informatics, 38 (5). ISSN 1868-1743

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Abstract

Histone deacetylase 6 (HDAC6) is unique hydrolase within HDAC family, having pleiotropic deacetylase activity against α-tubulin, cortactin and dynein. Comprehensively, HDAC6 controls cell motility, apoptosis and protein folding, whereas alterations in its structure and function are related to the pathogenesis of cancer, neurodegeneration and inflammation. To define structural motifs which guide HDAC6 selectivity, we developed and compared three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) models for HDAC1 and HDAC6 inhibitors. The reduction of the bias in conformer generation was supported by virtual docking study by using crystal structures of human HDAC1 and HDAC6 isoforms. Following these findings, the combined ligand-based and fragment-based drug design methodologies were used in the design of selective HDAC6 inhibitors. Group of the most promising novel ligands was selected based on the predicted HDAC6 selectivity, pharmacokinetic profile, synthetic tractability, and in silico cytotoxicity against the wide range of human cancer cell lines.

Item Type: Article
Uncontrolled Keywords: 3d-qsar,epidrugs,hdac6,rational drug design,structural biology,molecular medicine,drug discovery,computer science applications,organic chemistry ,/dk/atira/pure/subjectarea/asjc/1300/1315
Faculty \ School: Faculty of Science > School of Pharmacy
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Depositing User: LivePure Connector
Date Deposited: 13 Jun 2019 08:30
Last Modified: 09 Sep 2020 23:58
URI: https://ueaeprints.uea.ac.uk/id/eprint/71359
DOI: 10.1002/minf.201800083

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