AI Article Synopsis
- HDAC6 is a unique enzyme with diverse roles, influencing cell movement, death, and protein folding; its dysfunction is linked to cancer and other diseases.
- Researchers employed 3D-QSAR models to analyze and enhance the selectivity of HDAC6 inhibitors compared to HDAC1.
- By using a mix of drug design approaches, the team identified promising new compounds that show potential selectivity for HDAC6 and effectiveness against various cancer cell lines.
Article 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.
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| http://dx.doi.org/10.1002/minf.201800083 | DOI Listing |
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