title: Rational design and synthesis of 1,5-disubstituted tetrazoles as potent inhibitors of the MDM2-p53 interaction.
abstract: Using the computational pharmacophore-based ANCHOR.QUERY platform a new scaffold was discovered. Potent compounds evolved inhibiting the protein-protein interaction p53-MDM2. An extensive SAR study was performed based on our four-point pharmacophore model, yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and 2D-NMR-HSQC experiments.
authors.affiliation: Department of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Surmiak
authors.affiliation: Department of Pharmacy, Drug Design Department, University of Groningen, 9713AV Groningen, The Netherlands.
authors.forename: Constantinos G
authors.initials: CG
authors.lastname: Neochoritis
authors.affiliation: Department of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Musielak
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Twarda-Clapa
authors.affiliation: Department of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kurpiewska
authors.affiliation: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Dubin
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, 3501 Fifth Avenue, Biomedical Science Tower 3, Pittsburgh, PA 15260, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Camacho
authors.affiliation: Department of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland.
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
authors.affiliation: Department of Pharmacy, Drug Design Department, University of Groningen, 9713AV Groningen, The Netherlands. Electronic address: a.s.s.domling@rug.nl.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dömling
mesh_terms: D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D013777:Tetrazoles; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2