title: Discovery of a Novel HDAC2 Inhibitor by a Scaffold-Merging Hybrid Query.
abstract: Histone deacetylases (HDACs) are part of a vast family of enzymes with crucial roles in numerous biological processes, largely through their repressive influence on transcription, with serious implications in a variety of human diseases. Among different isoforms, human HDAC2 in particular draws attention as a promising target for the treatment of cancer and memory deficits associated with neurodegenerative diseases. Now the challenge is to obtain a compound that is structurally novel and truly selective to HDAC2 because most current HDAC2 inhibitors do not show isoforms selectivity and suffer from metabolic instability. In order to identify novel, and isoform-selective inhibitors for human HDAC2, we designed a shape-based hybrid query from multiple scaffolds of known chemical classes and validated it to be a more effective approach to discover diverse scaffolds than single-molecule query. The hybrid query-based screening rendered a hit compound with the N-benzylaniline scaffold which showed moderate inhibitory activity against HDAC2, and its chemical structure is diverse compared to known HDAC2 inhibitors. Notably, this compound shows the selectivity against the HDAC6, a Class II enzyme, thus has the potential to further develop into the class- and isoform-selective inhibitors. Our present study supplies an useful approach to identifying novel HDAC2 inhibitors, and can be extended to the inquires of other important biomedical targets as well.
authors.forename: Nikita
authors.initials: N
authors.lastname: Basant
authors.forename: Xionghao
authors.initials: X
authors.lastname: Lin
authors.forename: Terry-Elinor
authors.initials: TE
authors.lastname: Reid
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Karla
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, 2300 4th St. NW, Washington, DC 20059, USA. x.simon.wang@gmail.com.
authors.forename: Xiang S
authors.initials: XS
authors.lastname: Wang
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D062105:Molecular Docking Simulation
chemical_list: D000814:Aniline Compounds; D056572:Histone Deacetylase Inhibitors; C000607478:ST088357; D006655:Histone Deacetylases; C028443:benzylaniline