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 Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
- Myrianthopoulos, Vassilios Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
- Georgoulis, Anastasios Department of Biology, National and Kapodistrian University of Athens, 157 01 Panepistimiopolis, Zografou, Greece
- Lougiakis, Nikolaos Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
- Zantza, Iliana Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
- Lamprinidis, George Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
- Augsburger, Fiona Pharmacology, Section of Medicine, University of Fribourg, Ch. du Musée 18, 1700 Fribourg, Switzerland
- Marakos, Panagiotis Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
- Vorgias, Constantinos E. Department of Biology, National and Kapodistrian University of Athens, 157 01 Panepistimiopolis, Zografou, Greece
- Szabo, Csaba Pharmacology, Section of Medicine, University of Fribourg, Ch. du Musée 18, 1700 Fribourg, Switzerland
- Pouli, Nicole Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
- Papapetropoulos, Andreas Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece
- 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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16.08.2020
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.
- Faculty
- Faculté des sciences et de médecine
- Department
- Médecine 3ème année
- Language
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- English
- Classification
- Biological sciences
- License
- License undefined
- Identifiers
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- RERO DOC 329624
- DOI 10.3390/molecules25163739
- Persistent URL
- https://folia.unifr.ch/unifr/documents/309156
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