Screening of heteroaromatic scaffolds against cystathionine beta-synthase enables identification of substituted pyrazolo[3,4-c]pyridines as potent and selective orthosteric inhibitors
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Fantel, Anna-Maria
Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
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Myrianthopoulos, Vassilios
Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
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Georgoulis, Anastasios
Department of Biology, National and Kapodistrian University of Athens, 157 01 Panepistimiopolis, Zografou, Greece
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Lougiakis, Nikolaos
Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
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Zantza, Iliana
Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
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Lamprinidis, George
Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
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Augsburger, Fiona
Pharmacology, Section of Medicine, University of Fribourg, Ch. du Musée 18, 1700 Fribourg, Switzerland
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Marakos, Panagiotis
Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
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Vorgias, Constantinos E.
Department of Biology, National and Kapodistrian University of Athens, 157 01 Panepistimiopolis, Zografou, Greece
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Szabo, Csaba
Pharmacology, Section of Medicine, University of Fribourg, Ch. du Musée 18, 1700 Fribourg, Switzerland
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Pouli, Nicole
Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
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Papapetropoulos, Andreas
Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
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Mikros, Emmanuel
Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece - PharmaInformatics Unit, “Athena” Research and Innovation Center, Artemidos 6, 151 25 Maroussi, Greece
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Published in:
- Molecules. - 2020, vol. 25, no. 16, p. 3739
English
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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Faculty
- Faculté des sciences et de médecine
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Department
- Médecine 3ème année
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Language
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Classification
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Biological sciences
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License
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License undefined
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Identifiers
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Persistent URL
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https://folia.unifr.ch/unifr/documents/309156
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