Inhibitors of the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] identified by in silico molecular docking

Bioorg Med Chem Lett. 2013 Oct 15;23(20):5694-8. doi: 10.1016/j.bmcl.2013.08.016. Epub 2013 Aug 12.

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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / antagonists & inhibitors*
  • Acetyltransferases / metabolism
  • Binding Sites
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Kanamycin / chemistry
  • Kanamycin / metabolism
  • Kinetics
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism

Substances

  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Kanamycin
  • Acetyltransferases
  • aminoglycoside N(6')-acetyltransferase