Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors

Anna Maria Fantel, Vassilios Myrianthopoulos, Anastasios Georgoulis, Nikolaos Lougiakis, Iliana Zantza, George Lamprinidis, Fiona Augsburger, Panagiotis Marakos, Constantinos E. Vorgias, Csaba Szabo, Nicole Pouli, Andreas Papapetropoulos, Emmanuel Mikros

    Research output: Contribution to journalArticlepeer-review

    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.

    Original languageEnglish (US)
    Article number3739
    JournalMolecules
    Volume25
    Issue number16
    DOIs
    StatePublished - Aug 2020

    Keywords

    • 7-azido-4-methylcoumarin assay
    • Back-propagation DNN
    • Bateman module
    • Cystathionine β-synthase
    • Docking-scoring calculations
    • Hydrogen sulfide
    • Pyrazolo[3,4-c]pyridine
    • Sitemap algorithm
    • Thermal shift assay

    ASJC Scopus subject areas

    • Analytical Chemistry
    • Chemistry (miscellaneous)
    • Molecular Medicine
    • Pharmaceutical Science
    • Drug Discovery
    • Physical and Theoretical Chemistry
    • Organic Chemistry

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