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Eur J Med Chem. 2017 Jan 27;126:384-407. doi: 10.1016/j.ejmech.2016.11.029. Epub 2016 Nov 16.

Rational design and synthesis of 1,5-disubstituted tetrazoles as potent inhibitors of the MDM2-p53 interaction.

Author information

1
Department of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
2
Department of Pharmacy, Drug Design Department, University of Groningen, 9713AV Groningen, The Netherlands.
3
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.
4
Department of Computational and Systems Biology, University of Pittsburgh, 3501 Fifth Avenue, Biomedical Science Tower 3, Pittsburgh, PA 15260, USA.
5
Department of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland.
6
Department of Pharmacy, Drug Design Department, University of Groningen, 9713AV Groningen, The Netherlands. Electronic address: a.s.s.domling@rug.nl.

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.

PMID:
27907876
DOI:
10.1016/j.ejmech.2016.11.029
[Indexed for MEDLINE]

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