Analysis of Chemical Shift Changes Reveals the Binding Modes of Isoindolinone Inhibitors of the MDM2-p53 Interaction

Riedinger, Christiane; Endicott, Jane; Kemp, Stuart J.; Smyth, Lynette A.; Watson, Anna; Valeur, Eric; Golding, Bernard T.; Griffin, Roger J.; Hardcastle, Ian R.; Noble, M.E.M.; McDonnell, James M.

doi:10.1021/ja8062088

Cited by 99 publications

(49 citation statements)

References 27 publications

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“…As illustrated in Figure 4A, comparison of CSPs induced by fragment 1 to CSPs induced by fragments 2–5 highlight differences located all around the binding site, preventing any conclusion regarding the relative binding modes of the fragments. In another approach previously reported by Riedinger et al ., both the signs and the magnitudes of the CSPs are taken into account [39]. Nevertheless, the method does not allow the comparison of the ligand binding modes for fragments exhibiting very diverse CSP magnitudes.…”

Section: Resultsmentioning

confidence: 99%

Comparing Binding Modes of Analogous Fragments Using NMR in Fragment-Based Drug Design: Application to PRDX5

et al. 2014

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Fragment-based drug design is one of the most promising approaches for discovering novel and potent inhibitors against therapeutic targets. The first step of the process consists of identifying fragments that bind the protein target. The determination of the fragment binding mode plays a major role in the selection of the fragment hits that will be processed into drug-like compounds. Comparing the binding modes of analogous fragments is a critical task, not only to identify specific interactions between the protein target and the fragment, but also to verify whether the binding mode is conserved or differs according to the fragment modification. While X-ray crystallography is the technique of choice, NMR methods are helpful when this fails. We show here how the ligand-observed saturation transfer difference (STD) experiment and the protein-observed 15N-HSQC experiment, two popular NMR screening experiments, can be used to compare the binding modes of analogous fragments. We discuss the application and limitations of these approaches based on STD-epitope mapping, chemical shift perturbation (CSP) calculation and comparative CSP sign analysis, using the human peroxiredoxin 5 as a protein model.

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Section: Resultsmentioning

confidence: 99%

Comparing Binding Modes of Analogous Fragments Using NMR in Fragment-Based Drug Design: Application to PRDX5

et al. 2014

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“…A noteworthy example was the de novo preparation of the asparagine derivative 22 which resulted from both the benzylic oxidation and an oxazole cleavage. While the isoindolinone core has been common to medicinal compounds, 15 experimental therapeutics 16 and natural products, 17 its employment as a protecting group has received no attention. An asymmetric variant of the isoindolinone oxidation scheme is under investigation and the results will be reported in due course.…”

Section: Resultsmentioning

confidence: 99%

Selective alkylation/oxidation of N-substituted isoindolinone derivatives: Synthesis of N-phthaloylated natural and unnatural α-amino acid analogues

Patil

Luzzio

Ronnebaum

2017

Tetrahedron Letters

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The interchangeability of the isoindolinone group as a nitrogen protecting group for amino acid intermediates is demonstrated by the preparation of several natural and unnatural α-amino acid derivatives using a two-carbon N-isoindolinone (phthalimidine) scaffold. Using a selective benzylic oxidation, the N-isoindolinone group is then converted to the N-phthaloyl group for convenient removal (65–98%). For preparation of the isoindolinone products which were to be the substrates for benzylic oxidation, a range of side chains were installed on the isoindolinone-protected glycine equivalent on deprotonation to demonstrate the utility of the N-protected isoindolinone synthon (51–93%). While the ensuing benzylic oxidation is employed successfully for converting the N-isoindolinone group to the N-phthaloyl group in simple substrates, substrates bearing unsaturated or electron-rich side chains respond poorly to the oxidation.

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“…different adjacent pockets on the protein surface (Shuker et al 1996). This method has been further developed using different approaches in data analysis for the comparison of the binding modes of a series of analogous ligands (Medek et al 2000;Riedinger et al 2008). CSPs have been also used quantitatively in combination with computational methods.…”

Section: Introductionmentioning

confidence: 99%

Protein–ligand structure guided by backbone and side-chain proton chemical shift perturbations

et al. 2014

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The fragment-based drug design approach consists of screening libraries of fragment-like ligands, to identify hits that typically bind the protein target with weak affinity (100 μM-5 mM). The determination of the protein-fragment complex 3D structure constitutes a crucial step for uncovering the key interactions responsible for the protein-ligand recognition, and for growing the initial fragment into potent active compounds. The vast majority of fragments are aromatic compounds that induce chemical shift perturbations (CSP) on protein NMR spectra. These experimental CSPs can be quantitatively used to guide the ligand docking, through the comparison between experimental CSPs and CSP back-calculation based on the ring current effect. Here we implemented the CSP back-calculation into the scoring function of the program PLANTS. We compare the results obtained with CSPs measured either on amide or aliphatic protons of the human peroxiredoxin 5. We show that the different kinds of protons lead to different results for resolving the 3D structures of protein-fragment complexes, with the best results obtained with the Hα protons.

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Analysis of Chemical Shift Changes Reveals the Binding Modes of Isoindolinone Inhibitors of the MDM2-p53 Interaction

Cited by 99 publications

References 27 publications

Comparing Binding Modes of Analogous Fragments Using NMR in Fragment-Based Drug Design: Application to PRDX5

Comparing Binding Modes of Analogous Fragments Using NMR in Fragment-Based Drug Design: Application to PRDX5

Selective alkylation/oxidation of N-substituted isoindolinone derivatives: Synthesis of N-phthaloylated natural and unnatural α-amino acid analogues

Protein–ligand structure guided by backbone and side-chain proton chemical shift perturbations

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