{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:59:06Z","timestamp":1790355546464,"version":"4.1.0"},"reference-count":58,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T00:00:00Z","timestamp":1605657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Israel Science Foundatio","award":["1843\/17"],"award-info":[{"award-number":["1843\/17"]}]},{"name":"Israel Innovation Authority","award":["4632"],"award-info":[{"award-number":["4632"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The serine\/threonine kinase, GSK-3, is a promising drug discovery target for treating multiple pathological disorders. Most GSK-3 inhibitors that were developed function as ATP competitive inhibitors, with typical limitations in specificity, safety and drug-induced resistance. In contrast, substrate competitive inhibitors (SCIs), are considered highly selective, and more suitable for clinical practice. The development of SCIs has been largely neglected in the past because the ambiguous, undefined nature of the substrate-binding site makes them difficult to design. In this study, we used our previously described structural models of GSK-3 bound to SCI peptides, to design a pharmacophore model and to virtually screen the \u201cdrug-like\u201d Zinc database (~6.3 million compounds). We identified leading hits that interact with critical binding elements in the GSK-3 substrate binding site and are chemically distinct from known GSK-3 inhibitors. Accordingly, novel GSK-3 SCI compounds were designed and synthesized with IC50 values of~1\u20134 \u03bcM. Biological activity of the SCI compound was confirmed in cells and in primary neurons that showed increased \u03b2-catenin levels and reduced tau phosphorylation in response to compound treatment. We have generated a new type of small molecule GSK-3 inhibitors and propose to use this strategy to further develop SCIs for other protein kinases.<\/jats:p>","DOI":"10.3390\/ijms21228709","type":"journal-article","created":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T07:41:00Z","timestamp":1605685260000},"page":"8709","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Discovery and Design of Novel Small Molecule GSK-3 Inhibitors Targeting the Substrate Binding Site"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1651-5036","authenticated-orcid":false,"given":"Ido","family":"Rippin","sequence":"first","affiliation":[{"name":"Department of Human Molecular Genetics &amp; Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Netaly","family":"Khazanov","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley","family":"Ben Joseph","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics &amp; Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Kudinov","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics &amp; Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Berent","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics &amp; Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2333-2345","authenticated-orcid":false,"given":"Sara Melisa","family":"Arciniegas Ruiz","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics &amp; Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Marciano","sequence":"additional","affiliation":[{"name":"Israel Institute for Biological Research, Ness Ziona 7410001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Levy","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arie","family":"Gruzman","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0076-1355","authenticated-orcid":false,"given":"Hanoch","family":"Senderowitz","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Bar-Ilan University, Ramat Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8460-9686","authenticated-orcid":false,"given":"Hagit","family":"Eldar-Finkelman","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics &amp; Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1126\/science.1075762","article-title":"The protein kinase complement of the human genome","volume":"298","author":"Manning","year":"2002","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1126\/science.3291115","article-title":"The protein kinase family: Conserved features and deduced phylogeny of the catalytic domains","volume":"241","author":"Hanks","year":"1988","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1096\/fasebj.9.13.7557015","article-title":"How do protein kinases discriminate between serine\/threonine and tyrosine? 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