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

Andrea Carletta, Anaëlle Tilborg, Laurence Moineaux, Jérôme De Ruyck, Livia Basile, Loredana Salerno, Giuseppe Romeo, Johan Wouters, Salvatore Guccione

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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.

Original languageEnglish
Pages (from-to)447-454
Number of pages8
JournalActa Crystallographica Section B: Structural Science, Crystal Engineering and Materials
Volume71
DOIs
Publication statusPublished - 1 Aug 2015

Keywords

  • ab initio optimization
  • anticancer drugs
  • imidazole-based heme oxygenase inhibitors
  • molecular docking

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