Computational investigation of the binding mode of bis(hydroxylphenyl)arenes in 17β-HSD1: molecular dynamics simulations, MM-PBSA free energy calculations, and molecular electrostatic potential maps.

2.50
Hdl Handle:
http://hdl.handle.net/10033/216301
Title:
Computational investigation of the binding mode of bis(hydroxylphenyl)arenes in 17β-HSD1: molecular dynamics simulations, MM-PBSA free energy calculations, and molecular electrostatic potential maps.
Authors:
Negri, Matthias; Recanatini, Maurizio; Hartmann, Rolf W
Abstract:
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the last step of the estrogen biosynthesis, namely the reduction of estrone to the biologically potent estradiol. As such it is a potentially attractive drug target for the treatment of estrogen-dependent diseases like breast cancer and endometriosis. 17β-HSD1 belongs to the bisubstrate enzymes and exists as an ensemble of conformations. These principally differ in the region of the βFαG'-loop, suggesting a prominent role in substrate and inhibitor binding. Although several classes of potent non-steroidal 17β-HSD1 inhibitors currently exist, their binding mode is still unclear. We aimed to elucidate the binding mode of bis(hydroxyphenyl)arenes, a highly potent class of 17β-HSD1 inhibitors, and to rank these compounds correctly with respect to their inhibitory potency, two essential aspects in drug design. Ensemble docking experiments resulted in a steroidal binding mode for the closed enzyme conformations and in an alternative mode for the opened and occluded conformers with the inhibitors placed below the NADPH interacting with it synergically via π-π stacking and H-bond formation. Both binding modes were investigated by MD simulations and MM-PBSA binding free energy estimations using as representative member for this class compound 1 (50 nM). Notably, only the alternative binding mode proved stable and was energetically more favorable, while when simulated in the steroidal binding mode compound 1 was displaced from the active site. In parallel, ab initio studies of small NADPH-inhibitor complexes were performed, which supported the importance of the synergistic interaction between inhibitors and cofactor.
Affiliation:
Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2.3, 66123 Saarbrücken, Germany.
Citation:
Computational investigation of the binding mode of bis(hydroxylphenyl)arenes in 17β-HSD1: molecular dynamics simulations, MM-PBSA free energy calculations, and molecular electrostatic potential maps. 2011, 25 (9):795-811 J. Comput. Aided Mol. Des.
Journal:
Journal of computer-aided molecular design
Issue Date:
Sep-2011
URI:
http://hdl.handle.net/10033/216301
DOI:
10.1007/s10822-011-9464-7
PubMed ID:
21822722
Type:
Article
Language:
en
ISSN:
1573-4951
Appears in Collections:
Publications of the divsion Wirkstoffdesign und Optimierung (DDOP)

Full metadata record

DC FieldValue Language
dc.contributor.authorNegri, Matthiasen_GB
dc.contributor.authorRecanatini, Maurizioen_GB
dc.contributor.authorHartmann, Rolf Wen_GB
dc.date.accessioned2012-03-22T15:11:27Z-
dc.date.available2012-03-22T15:11:27Z-
dc.date.issued2011-09-
dc.identifier.citationComputational investigation of the binding mode of bis(hydroxylphenyl)arenes in 17β-HSD1: molecular dynamics simulations, MM-PBSA free energy calculations, and molecular electrostatic potential maps. 2011, 25 (9):795-811 J. Comput. Aided Mol. Des.en_GB
dc.identifier.issn1573-4951-
dc.identifier.pmid21822722-
dc.identifier.doi10.1007/s10822-011-9464-7-
dc.identifier.urihttp://hdl.handle.net/10033/216301-
dc.description.abstract17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the last step of the estrogen biosynthesis, namely the reduction of estrone to the biologically potent estradiol. As such it is a potentially attractive drug target for the treatment of estrogen-dependent diseases like breast cancer and endometriosis. 17β-HSD1 belongs to the bisubstrate enzymes and exists as an ensemble of conformations. These principally differ in the region of the βFαG'-loop, suggesting a prominent role in substrate and inhibitor binding. Although several classes of potent non-steroidal 17β-HSD1 inhibitors currently exist, their binding mode is still unclear. We aimed to elucidate the binding mode of bis(hydroxyphenyl)arenes, a highly potent class of 17β-HSD1 inhibitors, and to rank these compounds correctly with respect to their inhibitory potency, two essential aspects in drug design. Ensemble docking experiments resulted in a steroidal binding mode for the closed enzyme conformations and in an alternative mode for the opened and occluded conformers with the inhibitors placed below the NADPH interacting with it synergically via π-π stacking and H-bond formation. Both binding modes were investigated by MD simulations and MM-PBSA binding free energy estimations using as representative member for this class compound 1 (50 nM). Notably, only the alternative binding mode proved stable and was energetically more favorable, while when simulated in the steroidal binding mode compound 1 was displaced from the active site. In parallel, ab initio studies of small NADPH-inhibitor complexes were performed, which supported the importance of the synergistic interaction between inhibitors and cofactor.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Journal of computer-aided molecular designen_GB
dc.subject.mesh17-Hydroxysteroid Dehydrogenasesen_GB
dc.subject.meshBinding Sitesen_GB
dc.subject.meshDrug Designen_GB
dc.subject.meshEnzyme Inhibitorsen_GB
dc.subject.meshHumansen_GB
dc.subject.meshMolecular Dynamics Simulationen_GB
dc.subject.meshProtein Bindingen_GB
dc.subject.meshStatic Electricityen_GB
dc.subject.meshThermodynamicsen_GB
dc.titleComputational investigation of the binding mode of bis(hydroxylphenyl)arenes in 17β-HSD1: molecular dynamics simulations, MM-PBSA free energy calculations, and molecular electrostatic potential maps.en
dc.typeArticleen
dc.contributor.departmentPharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2.3, 66123 Saarbrücken, Germany.en_GB
dc.identifier.journalJournal of computer-aided molecular designen_GB
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