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.
Copyright © 2016. Published by Elsevier Masson SAS.
MeSH terms
-
Chemistry Techniques, Synthetic
-
Drug Design*
-
Humans
-
Models, Molecular
-
Protein Binding / drug effects
-
Protein Domains
-
Proto-Oncogene Proteins c-mdm2 / chemistry
-
Proto-Oncogene Proteins c-mdm2 / metabolism*
-
Structure-Activity Relationship
-
Tetrazoles / chemical synthesis*
-
Tetrazoles / chemistry
-
Tetrazoles / pharmacology*
-
Tumor Suppressor Protein p53 / chemistry
-
Tumor Suppressor Protein p53 / metabolism*
Substances
-
Tetrazoles
-
Tumor Suppressor Protein p53
-
Proto-Oncogene Proteins c-mdm2