title: Virtual medicinal chemistry: in silico pre-docking functional group transformation for discovery of novel inhibitors of botulinum toxin serotype A light chain.
abstract: A novel method for applying high-throughput docking to challenging metalloenzyme targets is described. The method utilizes information-based virtual transformation of library carboxylates to hydroxamic acids prior to docking, followed by compound acquisition, one-pot (two steps) chemical synthesis and in vitro screening. In two experiments targeting the botulinum neurotoxin serotype A metalloprotease light chain, hit rates of 32% and 18% were observed.
authors.affiliation: PanThera Biopharma, LLC, Aiea, HI 96701, USA. somalley@pantherabio.com
authors.forename: Sean
authors.initials: S
authors.lastname: O'Malley
authors.forename: Sina
authors.initials: S
authors.lastname: Sareth
authors.forename: Guan-Sheng
authors.initials: GS
authors.lastname: Jiao
authors.forename: Seongjin
authors.initials: S
authors.lastname: Kim
authors.forename: April
authors.initials: A
authors.lastname: Thai
authors.forename: Lynne
authors.initials: L
authors.lastname: Cregar-Hernandez
authors.forename: Linda
authors.initials: L
authors.lastname: McKasson
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Margosiak
authors.forename: Alan T
authors.initials: AT
authors.lastname: Johnson
mesh_terms: D001665:Binding Sites; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006877:Hydroxamic Acids / Q000737:chemistry; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012703:Serotyping; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D019274:Botulinum Toxins, Type A