Unveiling the "three finger pharmacophore" required for p53-MDM2 inhibition by saturation transfer difference NMR initial growth rates approach

Angulo, Jesus ORCID: https://orcid.org/0000-0001-7250-5639, Goffin, Sarah, Gandhi, Daivik, Searcey, Mark ORCID: https://orcid.org/0000-0003-2273-8949 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,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Pharmacy
Faculty of Science
Faculty of Science > School of Chemistry
UEA Research Groups: Faculty of Science > Research Groups > Drug Delivery and Pharmaceutical Materials (former - to 2017)
Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017)
Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Faculty of Science > Research Groups > Pharmaceutical Materials and Soft Matter
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Depositing User: Pure Connector
Date Deposited: 22 Mar 2016 09:27
Last Modified: 22 Oct 2022 00:50
URI: https://ueaeprints.uea.ac.uk/id/eprint/57776
DOI: 10.1002/chem.201600114

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