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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Résumé

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.

langue originaleAnglais
Pages (de - à)447-454
Nombre de pages8
journalActa Crystallographica Section B: Structural Science, Crystal Engineering and Materials
Volume71
Les DOIs
étatPublié - 1 août 2015

Empreinte digitale

Heme Oxygenase-1
Molecular modeling
imidazoles
inhibitors
Conformations
Crystal structure
crystal structure
analogs
structural analysis
crystallography
Crystallography
quantum mechanics
Quantum theory
Binding sites
Heme
Structural analysis
proteins
ligands
single crystals
Binding Sites

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title = "How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling",
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",
author = "Andrea Carletta and Ana{\"e}lle Tilborg and Laurence Moineaux and {De Ruyck}, J{\'e}r{\^o}me and Livia Basile and Loredana Salerno and Giuseppe Romeo and Johan Wouters and Salvatore Guccione",
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TY - JOUR

T1 - How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling

AU - Carletta, Andrea

AU - Tilborg, Anaëlle

AU - Moineaux, Laurence

AU - De Ruyck, Jérôme

AU - Basile, Livia

AU - Salerno, Loredana

AU - Romeo, Giuseppe

AU - Wouters, Johan

AU - Guccione, Salvatore

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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.

AB - 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.

KW - ab initio optimization

KW - anticancer drugs

KW - imidazole-based heme oxygenase inhibitors

KW - molecular docking

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U2 - 10.1107/S2052520615010410

DO - 10.1107/S2052520615010410

M3 - Article

VL - 71

SP - 447

EP - 454

JO - Acta Crystallographica Section B: Structural Science, Crystal Engineering and Materials

JF - Acta Crystallographica Section B: Structural Science, Crystal Engineering and Materials

SN - 2052-5206

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