Article ; Online: Design of Potent Panobinostat Histone Deacetylase Inhibitor Derivatives: Molecular Considerations for Enhanced Isozyme Selectivity between HDAC2 and HDAC8.
2018 Volume 38, Issue 3, Page(s) e1800080
Abstract: Histone Deacetylases (HDACs) are an important family of 18 isozymes, which are being pursued as drug targets for many types of disorders. HDAC2 and HDAC8 are two of the isozymes, which have been identified as drug targets for the design of anti-cancer, ... ...
| Abstract | Histone Deacetylases (HDACs) are an important family of 18 isozymes, which are being pursued as drug targets for many types of disorders. HDAC2 and HDAC8 are two of the isozymes, which have been identified as drug targets for the design of anti-cancer, neurodegenerative, immunological, and anti-parasitic agents. Design of potent HDAC2 and HDAC8 inhibitors will be useful for the therapeutic advances in many disorders. This work was undertaken to develop potent HDAC2 and HDAC8 inhibitors. A docking study was performed comparing panobinostat derivatives in both HDAC2 and HDAC8. Six of our derivatives showed stronger binding to HDAC2 than panobinostat, and two of our derivatives showed stronger binding to HDAC8 than panobinostat. We evaluated the molecular features, which improved potency of our inhibitors over panobinostat and also identified another molecular consideration, which could be used to enhance histone deacetylase inhibitor (HDACi) selectivity towards either the HDAC2 or HDAC8 isozymes. The results of this work can be used to assist future design of more potent and selective HDACi for HDAC2 and HDAC8. |
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| MeSH term(s) | Binding Sites ; Drug Design ; Histone Deacetylase 2/chemistry ; Histone Deacetylase 2/metabolism ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/chemistry ; Histone Deacetylases/metabolism ; Humans ; Molecular Docking Simulation ; Panobinostat/analogs & derivatives ; Protein Binding ; Repressor Proteins/chemistry ; Repressor Proteins/metabolism ; Substrate Specificity |
| Chemical Substances | Histone Deacetylase Inhibitors ; Repressor Proteins ; Panobinostat (9647FM7Y3Z) ; HDAC2 protein, human (EC 3.5.1.98) ; HDAC8 protein, human (EC 3.5.1.98) ; Histone Deacetylase 2 (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98) |
| Language | English |
| Publishing date | 2018-10-22 |
| Publishing country | Germany |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. |
| ZDB-ID | 2537668-8 |
| ISSN | 1868-1751 ; 1868-1743 |
| ISSN (online) | 1868-1751 |
| ISSN | 1868-1743 |
| DOI | 10.1002/minf.201800080 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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