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Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors

Cystathionine β-synthase (CBS) is a key enzyme in the production of the signaling molecule hydrogen sulfide, deregulation of which is known to contribute to a range of serious pathological states. Involvement of hydrogen sulfide in pathways of paramount importance for cellular homeostasis renders CB...

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Autores principales: Fantel, Anna-Maria, Myrianthopoulos, Vassilios, Georgoulis, Anastasios, Lougiakis, Nikolaos, Zantza, Iliana, Lamprinidis, George, Augsburger, Fiona, Marakos, Panagiotis, Vorgias, Constantinos E., Szabo, Csaba, Pouli, Nicole, Papapetropoulos, Andreas, Mikros, Emmanuel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465669/
https://www.ncbi.nlm.nih.gov/pubmed/32824311
http://dx.doi.org/10.3390/molecules25163739
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author Fantel, Anna-Maria
Myrianthopoulos, Vassilios
Georgoulis, Anastasios
Lougiakis, Nikolaos
Zantza, Iliana
Lamprinidis, George
Augsburger, Fiona
Marakos, Panagiotis
Vorgias, Constantinos E.
Szabo, Csaba
Pouli, Nicole
Papapetropoulos, Andreas
Mikros, Emmanuel
author_facet Fantel, Anna-Maria
Myrianthopoulos, Vassilios
Georgoulis, Anastasios
Lougiakis, Nikolaos
Zantza, Iliana
Lamprinidis, George
Augsburger, Fiona
Marakos, Panagiotis
Vorgias, Constantinos E.
Szabo, Csaba
Pouli, Nicole
Papapetropoulos, Andreas
Mikros, Emmanuel
author_sort Fantel, Anna-Maria
collection PubMed
description Cystathionine β-synthase (CBS) is a key enzyme in the production of the signaling molecule hydrogen sulfide, deregulation of which is known to contribute to a range of serious pathological states. Involvement of hydrogen sulfide in pathways of paramount importance for cellular homeostasis renders CBS a promising drug target. An in-house focused library of heteroaromatic compounds was screened for CBS modulators by the methylene blue assay and a pyrazolopyridine derivative with a promising CBS inhibitory potential was discovered. The compound activity was readily comparable to the most potent CBS inhibitor currently known, aminoacetic acid, while a promising specificity over the related cystathionine γ-lyase was identified. To rule out any possibility that the inhibitor may bind the enzyme regulatory domain due to its high structural similarity with cofactor s-adenosylmethionine, differential scanning fluorimetry was employed. A sub-scaffold search guided follow-up screening of related compounds, providing preliminary structure-activity relationships with respect to requisites for efficient CBS inhibition by this group of heterocycles. Subsequently, a hypothesis regarding the exact binding mode of the inhibitor was devised on the basis of the available structure-activity relationships (SAR) and a deep neural networks analysis and further supported by induced-fit docking calculations.
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spelling pubmed-74656692020-09-04 Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors Fantel, Anna-Maria Myrianthopoulos, Vassilios Georgoulis, Anastasios Lougiakis, Nikolaos Zantza, Iliana Lamprinidis, George Augsburger, Fiona Marakos, Panagiotis Vorgias, Constantinos E. Szabo, Csaba Pouli, Nicole Papapetropoulos, Andreas Mikros, Emmanuel Molecules Article Cystathionine β-synthase (CBS) is a key enzyme in the production of the signaling molecule hydrogen sulfide, deregulation of which is known to contribute to a range of serious pathological states. Involvement of hydrogen sulfide in pathways of paramount importance for cellular homeostasis renders CBS a promising drug target. An in-house focused library of heteroaromatic compounds was screened for CBS modulators by the methylene blue assay and a pyrazolopyridine derivative with a promising CBS inhibitory potential was discovered. The compound activity was readily comparable to the most potent CBS inhibitor currently known, aminoacetic acid, while a promising specificity over the related cystathionine γ-lyase was identified. To rule out any possibility that the inhibitor may bind the enzyme regulatory domain due to its high structural similarity with cofactor s-adenosylmethionine, differential scanning fluorimetry was employed. A sub-scaffold search guided follow-up screening of related compounds, providing preliminary structure-activity relationships with respect to requisites for efficient CBS inhibition by this group of heterocycles. Subsequently, a hypothesis regarding the exact binding mode of the inhibitor was devised on the basis of the available structure-activity relationships (SAR) and a deep neural networks analysis and further supported by induced-fit docking calculations. MDPI 2020-08-16 /pmc/articles/PMC7465669/ /pubmed/32824311 http://dx.doi.org/10.3390/molecules25163739 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fantel, Anna-Maria
Myrianthopoulos, Vassilios
Georgoulis, Anastasios
Lougiakis, Nikolaos
Zantza, Iliana
Lamprinidis, George
Augsburger, Fiona
Marakos, Panagiotis
Vorgias, Constantinos E.
Szabo, Csaba
Pouli, Nicole
Papapetropoulos, Andreas
Mikros, Emmanuel
Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors
title Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors
title_full Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors
title_fullStr Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors
title_full_unstemmed Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors
title_short Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors
title_sort screening of heteroaromatic scaffolds against cystathionine beta-synthase enables identification of substituted pyrazolo[3,4-c]pyridines as potent and selective orthosteric inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465669/
https://www.ncbi.nlm.nih.gov/pubmed/32824311
http://dx.doi.org/10.3390/molecules25163739
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