title: Synthesis of potent dishevelled PDZ domain inhibitors guided by virtual screening and NMR studies.
abstract: Dishevelled (Dvl) PDZ domains transduce Wnt signals from the membrane-bound receptor Frizzled to the downstream. As abnormal Wnt signaling has been implicated in tumorigenesis, the Dvl PDZ domain is a potential target for small-molecule inhibitors that block Wnt signaling at the Dvl level. We expanded our in silico search to examine the chemical space near previously developed PDZ binders and identified nine additional compounds bind to the Dvl PDZ. We then performed a quantitative structure-activity relationship (QSAR) analysis of these compounds and combined these results with structural studies of the PDZ domain in complex with the compounds to design and synthesize a group of new, further optimized compounds. Two rounds of synthesis and testing yielded a total of six compounds that have greatly improved binding affinity to the Dvl PDZ domain and most potent ones competitively displace Dapper peptide from the PDZ domain. In addition to providing more potent Dvl PDZ domain inhibitors, this study demonstrates that virtual screening and structural studies can be powerful tools in guiding the chemical synthesis hit-to-lead optimization stage during the drug discovery process.
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jufang
authors.initials: J
authors.lastname: Shan
authors.forename: Xinxin
authors.initials: X
authors.lastname: Zhang
authors.forename: Ju
authors.initials: J
authors.lastname: Bao
authors.forename: Robert
authors.initials: R
authors.lastname: Cassell
authors.forename: Jie J
authors.initials: JJ
authors.lastname: Zheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D000072261:Dishevelled Proteins; D015195:Drug Design; D051157:Frizzled Receptors / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D054731:PDZ Domains / Q000187:drug effects*; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors; D010750:Phosphoproteins; D054852:Small Molecule Libraries; D051153:Wnt Proteins