@article{3020778,
    title = "Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors",
    author = "Fantel, A.-M. and Myrianthopoulos, V. and Georgoulis, A. and Lougiakis, N. and Zantza, I. and Lamprinidis, G. and Augsburger, F. and Marakos, P. and Vorgias, C.E. and Szabo, C. and Pouli, N. and Papapetropoulos, A. and Mikros, E.",
    journal = "Molecules (Basel, Switzerland)",
    year = "2020",
    volume = "25",
    number = "16",
    publisher = "MDPI AG",
    doi = "10.3390/molecules25163739",
    keywords = "ademetionine;  cystathionine beta synthase;  enzyme inhibitor;  hydrogen sulfide;  pyrazole derivative;  pyrazolopyridine;  pyridine derivative, chemical structure;  chemistry;  human;  metabolism;  molecular model;  structure activity relation, Cystathionine beta-Synthase;  Enzyme Inhibitors;  Humans;  Hydrogen Sulfide;  Models, Molecular;  Molecular Structure;  Neural Networks, Computer;  Pyrazoles;  Pyridines;  S-Adenosylmethionine;  Structure-Activity Relationship",
    abstract = "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. © 2020 by the authors."
}