title: Unveiling the "Three-Finger Pharmacophore" Required for p53-MDM2 Inhibition by Saturation-Transfer Difference (STD) NMR Initial Growth-Rates Approach.
abstract: Inhibitors of the p53-MDM2 protein-protein interaction are emerging as a new and validated approach to treating cancer. Herein, we describe the synthesis and inhibitory evaluation of a series of isoquinolin-1-one analogues, and highlight the utility of an initial growth-rates saturation-transfer difference (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.
authors: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK. j.angulo@uea.ac.uk.
authors: Jesus
authors: J
authors: Angulo
authors: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors: Sarah A
authors: SA
authors: Goffin
authors: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors: Daivik
authors: D
authors: Gandhi
authors: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.|School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors: Mark
authors: M
authors: Searcey
authors: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK. l.howell@uea.ac.uk.
authors: Lesley A
authors: LA
authors: Howell
mesh_terms: D001665:Binding Sites; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D011506:Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: NMR spectroscopy; cancer; molecular modelling; p53-MDM2; proteins; saturation-transfer difference NMR spectroscopy