Τίτλος:
Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Fantel, A.-M.
Myrianthopoulos, V.
Georgoulis, A.
Lougiakis, N.
Zantza, I.
Lamprinidis, G.
Augsburger, F.
Marakos, P.
Vorgias, C.E.
Szabo, C.
Pouli, N.
Papapetropoulos, A.
Mikros, E.
Περιοδικό:
Molecules (Basel, Switzerland)
Λέξεις-κλειδιά:
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
DOI:
10.3390/molecules25163739
