{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T12:54:54Z","timestamp":1771073694929,"version":"3.50.1"},"reference-count":58,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2020,8,16]],"date-time":"2020-08-16T00:00:00Z","timestamp":1597536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003447","name":"State Scholarships Foundation","doi-asserted-by":"publisher","award":["MIS-5000432"],"award-info":[{"award-number":["MIS-5000432"]}],"id":[{"id":"10.13039\/501100003447","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NSRF 2014-2020","award":["MIS-5002550"],"award-info":[{"award-number":["MIS-5002550"]}]},{"DOI":"10.13039\/501100004343","name":"Stavros Niarchos Foundation","doi-asserted-by":"publisher","award":["not applicable"],"award-info":[{"award-number":["not applicable"]}],"id":[{"id":"10.13039\/501100004343","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cystathionine \u03b2-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 \u03b3-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.<\/jats:p>","DOI":"10.3390\/molecules25163739","type":"journal-article","created":{"date-parts":[[2020,8,17]],"date-time":"2020-08-17T06:33:20Z","timestamp":1597646000000},"page":"3739","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors"],"prefix":"10.3390","volume":"25","author":[{"given":"Anna-Maria","family":"Fantel","sequence":"first","affiliation":[{"name":"Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8359-9634","authenticated-orcid":false,"given":"Vassilios","family":"Myrianthopoulos","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasios","family":"Georgoulis","sequence":"additional","affiliation":[{"name":"Department of Biology, National and Kapodistrian University of Athens, 157 01 Panepistimiopolis, Zografou, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0582-4415","authenticated-orcid":false,"given":"Nikolaos","family":"Lougiakis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, 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Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Pouli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4253-5930","authenticated-orcid":false,"given":"Andreas","family":"Papapetropoulos","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5984-5169","authenticated-orcid":false,"given":"Emmanuel","family":"Mikros","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National and Kapodistrian University of Athens, 157 74 Panepistimiopolis, Zografou, Greece"},{"name":"PharmaInformatics Unit, \u201cAthena\u201d 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