title: Histone deacetylases: structural determinants of inhibitor selectivity.
abstract: Histone deacetylases (HDACs) are epigenetic targets with an important role in cancer, neurodegeneration, inflammation, and metabolic disorders. Although clinically effective HDAC inhibitors have been developed, the design of inhibitors with the desired isoform(s) selectivity remains a challenge. Selective inhibitors could help clarify the function of each isoform, and provide therapeutic agents having potentially fewer adverse effects. Crystal structures of several HDACs have been reported, enabling structure-based drug design and providing important information to understand enzyme function. Here, we provide a comprehensive review of the structural information available on HDACs, discussing both conserved and isoform-specific structural and mechanistic features. We focus on distinctive aspects that help rationalize inhibitor selectivity, and provide structure-based recommendations for achieving the desired selectivity.
authors: Life Sciences Department, University of Modena and Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
authors: Carmina
authors: C
authors: Micelli
authors: Life Sciences Department, University of Modena and Reggio Emilia, Via Campi 183, 41125 Modena, Italy. Electronic address: giulio.rastelli@unimore.it.
authors: Giulio
authors: G
authors: Rastelli
mesh_terms: D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D008024:Ligands; D006655:Histone Deacetylases