title: Structural basis for the design and synthesis of selective HDAC inhibitors.
abstract: Histone Deacetylases are considered promising targets for cancer epigenetic therapy, and small molecules able to modulate their biological function have recently gained an increasing interest as potential anticancer agents. In spite of their potential application in cancer therapy, most HDAC inhibitors unselectively bind the several HDAC isoforms, giving rise to different side-effects. In this context, we have traced out the structural elements responsible of selective binding for the therapeutically relevant different HDAC isoforms. The structural analysis has been carried out by molecular modeling, docking in the binding pockets of HDAC1-4 and HDAC6-8, 36 inhibitors presenting a well defined selectivity for the different isoforms. As quick proof of evidence, we have designed, synthesized and experimentally tested three selective ligands. The experimental data suggest that the obtained structural guidelines can be useful tools for the rational design of new potent inhibitors against selected HDAC isoforms.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Di Micco
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Chini
authors.forename: Stefania
authors.initials: S
authors.lastname: Terracciano
authors.forename: Ines
authors.initials: I
authors.lastname: Bruno
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D008024:Ligands; D020033:Protein Isoforms; D006655:Histone Deacetylases