title: Inhibitors of the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] identified by in silico molecular docking.
abstract: AAC(6')-Ib is an important aminoglycoside resistance enzyme to target with enzymatic inhibitors. An in silico screening approach was used to identify potential inhibitors from the ChemBridge library. Several compounds were identified, of which two of them, 4-[(2-{[1-(3-methylphenyl)-4,6-dioxo-2-thioxotetrahydro-5(2H)-pyrimidinylidene]methyl}phenoxy)methyl]benzoic acid and 2-{5-[(4,6-dioxo-1,3-diphenyl-2-thioxotetrahydro-5(2H)-pyrimidinylidene)methyl]-2-furyl}benzoic acid, showed micromolar activity in inhibiting acetylation of kanamycin A. These compounds are predicted to bind the aminoglycoside binding site of AAC(6')-Ib and exhibited competitive inhibition against kanamycin A.
authors.affiliation: Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, 800 N State College Boulevard, Fullerton, CA 92834-6850, United States. Electronic address: lidlin@csu.fullerton.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Lin
authors.forename: Tung
authors.initials: T
authors.lastname: Tran
authors.forename: Christina
authors.initials: C
authors.lastname: Adams
authors.forename: Jamal Y
authors.initials: JY
authors.lastname: Alam
authors.forename: Steven R
authors.initials: SR
authors.lastname: Herron
authors.forename: Marcelo E
authors.initials: ME
authors.lastname: Tolmasky
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D007612:Kanamycin / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D007612:Kanamycin; D000123:Acetyltransferases; C056532:aminoglycoside N(6')-acetyltransferase
keywords: 5,5′-dithiobis(2-nitrobenzoic acid); AAC(6′)-Ib; Acetyltransferase; Aminoglycoside modifying enzymes; Aminoglycoside resistance; DMSO; DTNB; Enterobacteria; Inhibitor; Klebsiella; V(i); acetyl CoA; acetyl coenzyme A; aminoglycoside 6′-N-acetyltransferase type Ib; dimethyl sulfoxide; initial velocity