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 2020-08-16 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. application/pdf https://folia.unifr.ch/global/documents/309156 https://folia.unifr.ch/documents/309156/files/sza_shs.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.3390/molecules25163739 info:eu-repo/semantics/openAccess License undefined Molecules. - 2020, vol. 25, no. 16, p. 3739 info:eu-repo/classification/udc/57 Screening of heteroaromatic scaffolds against cystathionine beta-synthase enables identification of substituted pyrazolo[3,4-c]pyridines as potent and selective orthosteric inhibitors http://purl.org/coar/resource_type/c_6501