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

doi:10.1107/S2052520615010410

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

Unit of theoretical and structural physico-chemistry

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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 language	English
Pages (from-to)	447-454
Number of pages	8
Journal	Acta Crystallographica Section B: Structural Science, Crystal Engineering and Materials
Volume	71
DOIs	https://doi.org/10.1107/S2052520615010410
Publication status	Published - 1 Aug 2015

Keywords

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

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10.1107/S2052520615010410

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Carletta, A., Tilborg, A., Moineaux, L., De Ruyck, J., Basile, L., Salerno, L., Romeo, G., Wouters, J., & Guccione, S. (2015). How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling. Acta Crystallographica Section B: Structural Science, Crystal Engineering and Materials, 71, 447-454. https://doi.org/10.1107/S2052520615010410

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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.",

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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Carletta, A, Tilborg, A, Moineaux, L, De Ruyck, J, Basile, L, Salerno, L, Romeo, G, Wouters, J & Guccione, S 2015, 'How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling', Acta Crystallographica Section B: Structural Science, Crystal Engineering and Materials, vol. 71, pp. 447-454. https://doi.org/10.1107/S2052520615010410

How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling. / Carletta, Andrea; Tilborg, Anaëlle; Moineaux, Laurence et al.
In: Acta Crystallographica Section B: Structural Science, Crystal Engineering and Materials, Vol. 71, 01.08.2015, p. 447-454.

Research output: Contribution to journal › Article › peer-review

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.

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KW - anticancer drugs

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Carletta A, Tilborg A, Moineaux L, De Ruyck J, Basile L, Salerno L et al. How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling. Acta Crystallographica Section B: Structural Science, Crystal Engineering and Materials. 2015 Aug 1;71:447-454. doi: 10.1107/S2052520615010410

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

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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

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Physical Chemistry and characterization(PC2)

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