{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:33:05Z","timestamp":1791174785866,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2011,5,27]],"date-time":"2011-05-27T00:00:00Z","timestamp":1306454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2011,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Shank is the central scaffolding protein of the postsynaptic density (PSD) protein complex found in cells of the central nervous system. Cellular studies indicate a prominent role of the protein in the organization of the PSD, in the development of neuronal morphology, in neuronal signaling, and in synaptic plasticity, thus linking Shank functions to the molecular basis of learning and memory. Mutations in the Shank gene have been found in several neuronal disorders including mental retardation, typical autism, and Asperger syndrome. Shank is linked to the PSD complex via its PDZ domain that binds to the C\u2010terminus of guanylate\u2010kinase\u2010associated protein (GKAP). Here, small\u2010molecule inhibitors of Shank3 PDZ domain are developed. A fluorescence polarization assay based on an identified high\u2010affinity peptide is established, and tetrahydroquinoline carboxylates are identified as inhibitors of this protein\u2013protein interaction. Chemical synthesis via a hetero\u2010Diels\u2013Alder strategy is employed for hit optimization, and structure\u2013activity relationship studies are performed. Best hits possess\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    values in the 10\u2005\u03bc\n                    <jats:sc>M<\/jats:sc>\n                    range, and binding to the PDZ domain is confirmed by\n                    <jats:sup>1<\/jats:sup>\n                    H,\n                    <jats:sup>15<\/jats:sup>\n                    N HSQC\u2005NMR experiments. One of the hits crystallizes with the Shank3 PDZ domain. The structure, analyzed at a resolution of 1.85\u2005\u00c5, reveals details of the binding mode. Finally, binding to PDZ domains of PSD\u201095, syntrophin, and DVL3 was studied using\n                    <jats:sup>1<\/jats:sup>\n                    H,\n                    <jats:sup>15<\/jats:sup>\n                    N HSQC\u2005NMR spectroscopy.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.201100094","type":"journal-article","created":{"date-parts":[[2011,5,27]],"date-time":"2011-05-27T10:21:59Z","timestamp":1306491719000},"page":"1411-1422","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Discovery, Structure\u2013Activity Relationship Studies, and Crystal Structure of Nonpeptide Inhibitors Bound to the Shank3 PDZ 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