title: Flexibility is important for inhibition of the MDM2/p53 protein-protein interaction by cyclic β-hairpins.
abstract: Protein-protein interactions that have large, flat and featureless binding sites are difficult drug targets. In the development of their modulators conventional drug discovery strategies are often unsuccessful. Gaining a detailed understanding of the binding mode of protein-protein interaction inhibitors is therefore of vast importance for their future pharmaceutical use. The MDM2/p53 protein pair is a highly promising target for cancer treatment. Disruption of the protein complex using p53 α-helix mimetics has been shown to be a successful strategy to control p53 activity. To gain further insight into the binding of inhibitors to MDM2, the flexibility of four cyclic β-hairpins that act as α-helical mimetics and potential MDM2/p53 interaction inhibitors was investigated in relation to their inhibitory activity. MDM2-binding of the mimetics was determined using fluorescence polarization and surface plasmon resonance assays, whereas their conformation and dynamics in solution was described by the combined experimental and computational NAMFIS analysis. Molecular flexibility was shown to be important for the activity of the cyclic β-hairpin based MDM2 inhibitors.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, SE-41296 Gothenburg, Sweden. grotli@chem.gu.se mate@chem.gu.se.
authors.forename: Emma
authors.initials: E
authors.lastname: Danelius
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, SE-41296 Gothenburg, Sweden. grotli@chem.gu.se mate@chem.gu.se.
authors.forename: Mariell
authors.initials: M
authors.lastname: Pettersson
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, SE-41296 Gothenburg, Sweden. grotli@chem.gu.se mate@chem.gu.se.
authors.forename: Matilda
authors.initials: M
authors.lastname: Bred
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: Jaeki
authors.initials: J
authors.lastname: Min
authors.affiliation: Molecular Interaction Analysis Shared Resource, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: M Brett
authors.initials: MB
authors.lastname: Waddell
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, SE-41296 Gothenburg, Sweden. grotli@chem.gu.se mate@chem.gu.se.
authors.forename: Morten
authors.initials: M
authors.lastname: Grøtli
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, SE-41296 Gothenburg, Sweden. grotli@chem.gu.se mate@chem.gu.se and Swedish NMR Centre, Medicinaregatan 5, SE-41390 Gothenburg, Sweden.
authors.forename: Mate
authors.identifier: http://orcid.org/0000-0003-0359-5970
authors.initials: M
authors.lastname: Erdelyi
mesh_terms: D015195:Drug Design; D008958:Models, Molecular; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D000072756:Protein Conformation, alpha-Helical; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D057786:Peptidomimetics; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2