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

Jesus Angulo (Lead Author), Sarah Goffin, Daivik Gandhi, Mark Searcey, Lesley Howell (Lead Author)

Research output: Contribution to journalArticlepeer-review

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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.
Original languageEnglish
Pages (from-to)5858-5862
Number of pages5
JournalChemistry - A European Journal
Volume22
Issue number17
Early online date7 Mar 2016
DOIs
Publication statusPublished - 18 Apr 2016

Keywords

  • saturation-transfer difference NMR
  • p53-MDM2
  • cancer
  • protein-protein interactions
  • molecular modelling

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