Evaluation of Solvent Accessibility Epitopes for Different Dehydrogenase Inhibitors

Ludwig, Christian; Michiels, Paulus J. A.; Lodi, Alessia; Ride, John; Bunce, Christopher M.; Günther, Ulrich L.

doi:10.1002/cmdc.200800110

Cited by 19 publications

(18 citation statements)

References 27 publications

(36 reference statements)

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“…Recently, Günther and coworkers have described a modified version of the experiment [187], denoted SALMON (Solvent accessibility, ligand binding, and mapping of ligand orientation by NMR spectroscopy), that applied using small mixing times for protein-mediated magnetization transfer allows the mapping of binding epitopes on the ligand. Several recent applications have been described using such modified experiment [188][189][190]. Besides, a recent optimization of the pulse sequence results in significantly reduced NMR acquisition times [191].…”

Section: Waterlogsymentioning

confidence: 99%

NMR Screening and Hit Validation in Fragment Based Drug Discovery

Campos-Olivas

2011

CTMC

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Over the past three decades nuclear magnetic resonance spectroscopy has been developed into a mature technique for the characterization of interactions of small molecule ligands with their corresponding protein and nucleic acid receptors. In fact, a significant number of industrial and academic laboratories employ NMR for screening small molecule compound collections for binding to defined macromolecular targets, thus potentially providing initial, low affinity hits for a fragment-based approach in the drug discovery process. NMR is also applied to interrogate hits obtained by high throughput screening using biochemical assays and by virtual screening methods, for their ability to physically interact with the target receptor. In favorable cases a variety of NMR-based methods can also provide essential information to validate the hit, rank the different hits according to affinity, and to structurally analyze the ligand-target complex, thus providing essential information for structure-based optimization and medicinal chemistry. In this review a comprehensive overview of the large variety of NMR methods to study interactions between small molecule ligands and macromolecular receptors is provided, summarizing the physico-chemical bases of the different receptor- and ligand-observed experiments. The application of these methods for compound library screening and hit validation, with special emphasis on their contribution to fragment-based drug discovery strategies, is illustrated by recent examples selected from the literature and work in my laboratory.

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Section: Waterlogsymentioning

confidence: 99%

NMR Screening and Hit Validation in Fragment Based Drug Discovery

Campos-Olivas

2011

CTMC

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“…The most commonly used techniques which observe ligand resonances employ magnetization transfer by the nuclear Overhauser effect (NOE). These include the transferred NOE (19), NOE pumping (20) and reverse pumping (21), saturation transfer (STD-NMR) (22)(23)(24), waterLOGSY (25,26), derivation of solvent accessibility epitopes from waterLOGSY experiments (SALMON) (27,28) and interligand NOEs between two competitively binding molecules (INPHARMA) (29,30).…”

Section: Tins Excess Yes No Yesmentioning

confidence: 99%

“…While the initial waterLOGSY experiment seemed to be limited to the identification of binders vs non-binders recent work showed that waterLOGSY can be used to probe for bulk water accessibility to derive the orientation of a bound ligand. This approach has been termed SALMON (Solvent Accessibility and protein Ligand binding studied by NMR Spectroscopy) (27,28). To be able to derive a solvent accessibility epitope from waterLOGSY spectra shorter mixing times have to be chosen to avoid blurring of of the epitope by massive spin diffusion.…”

Section: Waterlogsy and Salmonmentioning

confidence: 99%

“…WaterLOGSY excess yes no yes Weakly binding com-pounds are identified through negative NOEs originating from the water resonance (25,26). SALMON excess yes yes yes Similar experimental conditions to waterLOGSY; a solvent accessibility epitope can be derived through use of short mixing times (27,28). Transferred NOEs excess no no no Information on protein/ligand interaction as well as conformation of bound ligand can be derived from cross peak analysis (19,45,47,48 (31,34,37).…”

Section: Introductionmentioning

confidence: 99%

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Ligand based NMR methods for drug discovery

Ludwig¹

2009

Front Biosci

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NMR has a long history in drug discovery and hit-to-lead optimization. Compared to many other methods NMR has the advantage of combining structural and functional parameters to characterize protein inhibitor interactions. NMR methods used in this context can be split into two categories; protein based experiments using isotopically labelled protein samples and a broad range of ligand based methods. Recently, there has been a strong emphasis on so-called ligand-based methods which offer a broad range of options to determine binding epitopes. Ligand-based methods are attractive because they are broadly applicable, impose few constraints on the composition of the target protein and don't require isotopic labeling of the protein or ligands. Such experiments include diffusion experiments, saturation transfer difference (STD-NMR), NOE pumping, waterLOGSY, SALMON, transferred-NOE and INPHARMA. Ligand-based NMR methods have been employed in screening and in lead optimization. One key advantage arises from their capability to pick up specific interactions for compounds of relatively low affinity and their ability to provide limited structural information without any need of crystallization or isotopic labeling.

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“…Particularly, in early stages of the FBLD process where often medium-to-weak binders are encountered, NMR spectroscopy is particularly powerful as it is not only a very sensitive detection technique but also provides additional information about binding modes and orientations of bound ligands (mapping of the binding site). Several experiments have thus been developed in the recent past (INPHARMA 9 and SALMON 10 ). Most recently, we have devised an NMR pulse sequence for the investigation of protein ligand interactions.…”

Section: Introductionmentioning

confidence: 99%

Toward Rational Fragment-Based Lead Design without 3D Structures

et al. 2012

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Fragment-based lead discovery (FBLD) has become a prime component of the armamentarium of modern drug design programs. FBLD identifies low molecular weight ligands that weakly bind to important biological targets. Three-dimensional structural information about the binding mode is provided by X-ray crystallography or NMR spectroscopy and is subsequently used to improve the lead compounds. Despite tremendous success rates, FBLD relies on the availability of high-resolution structural information, still a bottleneck in drug discovery programs. To overcome these limitations, we recently demonstrated that the meta-structure approach provides an alternative route to rational lead identification in cases where no 3D structure information about the biological target is available. Combined with information-rich NMR data, this strategy provides valuable information for lead development programs. We demonstrate with several examples the feasibility of the combined NMR and meta-structure approach to devise a rational strategy for fragment evolution without resorting to highly resolved protein complex structures.

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Evaluation of Solvent Accessibility Epitopes for Different Dehydrogenase Inhibitors

Cited by 19 publications

References 27 publications

NMR Screening and Hit Validation in Fragment Based Drug Discovery

NMR Screening and Hit Validation in Fragment Based Drug Discovery

Ligand based NMR methods for drug discovery

Toward Rational Fragment-Based Lead Design without 3D Structures

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