Development of quinone analogues as dynamin GTPase inhibitors

Eur J Med Chem. 2014 Oct 6:85:191-206. doi: 10.1016/j.ejmech.2014.06.070. Epub 2014 Jul 5.

Abstract

Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 μM inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 μM respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 μM.

Keywords: Dynamin; Dynamin inhibitors; Endocytosis; Modelling; Quinones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Clathrin / metabolism
  • Drug Evaluation, Preclinical
  • Dynamin I / antagonists & inhibitors*
  • Dynamin I / chemistry
  • Dynamin I / metabolism
  • Endocytosis / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • GTP Phosphohydrolases / antagonists & inhibitors*
  • Humans
  • Molecular Docking Simulation
  • Protein Conformation
  • Quinones / chemistry*
  • Structure-Activity Relationship

Substances

  • Clathrin
  • Enzyme Inhibitors
  • Quinones
  • Dynamin I
  • GTP Phosphohydrolases