How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling

Acta Crystallogr B Struct Sci Cryst Eng Mater. 2015 Aug;71(Pt 4):447-54. doi: 10.1107/S2052520615010410. Epub 2015 Jul 14.

Abstract

Heme oxygenase-1 (HO-1) inhibition is associated with antitumor activity. Imidazole-based analogues show effective and selective inhibitory potency of HO-1. In this work, five single-crystal structures of four imidazole-based compounds are presented, with an in-depth structural analysis. In order to study the influence of the conformation of the ligands on binding to protein, conformational data from crystallography are compared with quantum mechanics analysis and molecular docking studies. Molecular docking of imidazole-based analogues in the active site of HO-1 is in good agreement with the experimental structures. Inhibitors interact with the heme cofactor and a hydrophobic pocket (Met34, Phe37, Val50, Leu147 and Phe214) in the HO-1 binding site. An alternate binding mode can be hypothesized for some inhibitors in the series.

Keywords: ab initio optimization; anticancer drugs; imidazole-based heme oxygenase inhibitors; molecular docking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Heme Oxygenase-1 / antagonists & inhibitors
  • Heme Oxygenase-1 / chemistry*
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Models, Molecular*
  • Protein Binding
  • Protein Conformation / drug effects
  • Quantum Theory

Substances

  • Enzyme Inhibitors
  • Imidazoles
  • imidazole
  • Heme Oxygenase-1