Unveiling the "Three Finger Pharmacophore" required for p53-MDM2 Inhibition by Saturation Transfer Difference NMR Initial Growth Rates Approach

Angulo, Jesus, Goffin, Sarah, Gandhi, Daivik, Searcey, Mark and Howell, Lesley (2016) Unveiling the "Three Finger Pharmacophore" required for p53-MDM2 Inhibition by Saturation Transfer Difference NMR Initial Growth Rates Approach. Chemistry - A European Journal, 22 (17). pp. 5858-5862. ISSN 0947-6539

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Abstract

Inhibitors of the p53-MDM2 protein-protein interaction are emerging as a novel and validated approach to treating cancer. In this work we describe the synthesis and inhibitory evaluation of a series of isoquinolin-1-one analogues, and highlight the utility of an initial growth rates STD NMR approach supported by protein-ligand docking to investigate p53-MDM2 inhibition. The approach is illustrated by the study of compound 1, providing key insights into the binding mode of this kind of MDM2 ligands and, more importantly, readily unveiling the previously proposed three finger pharmacophore requirement for p53-MDM2 inhibition.

Item Type: Article
Uncontrolled Keywords: saturation-transfer difference nmr,p53-mdm2,cancer,protein-protein interactions,molecular modelling
Faculty \ School: Faculty of Science > School of Pharmacy
Faculty of Science
Faculty of Science > School of Chemistry
Related URLs:
Depositing User: Pure Connector
Date Deposited: 22 Mar 2016 09:27
Last Modified: 31 Oct 2019 14:48
URI: https://ueaeprints.uea.ac.uk/id/eprint/57776
DOI: 10.1002/chem.201600114

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