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

doi:10.3390/molecules25163739

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Journal article

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

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