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How does binding of imidazole‐based inhibitors to heme oxygenase‐1 influence their conformation? Insights combining crystal structures and molecular modelling
Author(s) -
Carletta Andrea,
Tilborg Anaëlle,
Moineaux Laurence,
de Ruyck Jérôme,
Basile Livia,
Salerno Loredana,
Romeo Giuseppe,
Wouters Johan,
Guccione Salvatore
Publication year - 2015
Publication title -
acta crystallographica section b
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.604
H-Index - 33
ISSN - 2052-5206
DOI - 10.1107/s2052520615010410
Subject(s) - imidazole , chemistry , docking (animal) , stereochemistry , molecular mechanics , heme , molecular model , heme oxygenase , binding site , active site , molecular dynamics , cofactor , enzyme , computational chemistry , biochemistry , medicine , nursing
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.