title: Computational exploration of zinc binding groups for HDAC inhibition.
abstract: Histone deacetylases (HDACs) have emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders, is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed.
authors.affiliation: Lab of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Liping
authors.initials: L
authors.lastname: Xu
authors.forename: Olaf
authors.initials: O
authors.lastname: Wiest
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009942:Organometallic Compounds; D006655:Histone Deacetylases; D015032:Zinc