A5052695748- Advanced NMR Techniques and Applications
- Electron Spin Resonance Studies
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Solid-state spectroscopy and crystallography
- Atomic and Subatomic Physics Research
- Molecular spectroscopy and chirality
- NMR spectroscopy and applications
- Biochemical and Molecular Research
- Cancer therapeutics and mechanisms
- Chemical Reaction Mechanisms
- Synthesis and Characterization of Heterocyclic Compounds
- Computational Drug Discovery Methods
- Advanced Proteomics Techniques and Applications
- Advanced Biosensing Techniques and Applications
- Multicomponent Synthesis of Heterocycles
- Alzheimer's disease research and treatments
- Signaling Pathways in Disease
- Bioinformatics and Genomic Networks
- Analytical Chemistry and Sensors
- RNA and protein synthesis mechanisms
- HIV Research and Treatment
- Nonlinear Optical Materials Research
- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
ETH Zurich
2018-2025
Nexen (Canada)
2024
École Polytechnique Fédérale de Lausanne
2019-2023
Board of the Swiss Federal Institutes of Technology
2023
Theologische Hochschule Chur
2021
Charles Humbert 8
2021
Universidad Complutense de Madrid
1999
While nuclear magnetic resonance (NMR) is regarded as a reference in fragment-based drug design, its implementation high-throughput manner limited by lack of sensitivity resulting long acquisition times and high micromolar sample concentrations. Several hyperpolarization approaches could, principle, improve the NMR also research. However, photochemically induced dynamic polarization (photo-CIDNP) only method that directly applicable aqueous solution agile for scalable using off-the-shelf...
Fragment-based drug design is a well-established strategy for rational design, with nuclear magnetic resonance (NMR) on high-field spectrometers as the method of reference screening and hit validation. However, NMR are not only expensive, but require specialized maintenance, dedicated space, depend liquid helium cooling which became critical over recurring global shortages. We propose an alternative to by applying recently developed approach fragment photoinduced hyperpolarized cryogen-free...
Benchtop NMR is becoming an increasingly important tool, sometimes providing a simple and low-cost alternative to high-field NMR. The Achilles heel of even more critically benchtop its limited sensitivity. However, when combined with hyperpolarization techniques, the sensitivity boost can provide excellent that make compatible affinity studies for drug discovery. Hyperpolarization by dissolution dynamic nuclear polarization (dDNP) provides route enhancing 13C magnetic resonance (NMR) than 5...
The binding affinity determination of protein–ligand complexes is a cornerstone drug design. State-of-the-art techniques are limited by lengthy and expensive processes. Building upon our recently introduced novel screening method utilizing photochemically induced dynamic nuclear polarization (photo-CIDNP) NMR, we provide the methodological framework to determine affinities within 5–15 min using 0.1 mg protein. accuracy demonstrated for constants peptides PDZ domain fragment ligands protein...
Photo-chemically induced nuclear polarization yields to NMR signal-to-noise enhancement and can be tuned by chemical modification of one the radical-pair partners.
Abstract The complex kinetics of disease-related amyloid aggregation proteins such as α-Synuclein (α-Syn) in Parkinson’s disease and Aβ42 Alzheimer’s include primary nucleation, fibril elongation secondary nucleation. latter can be a key accelerator the process. It has been demonstrated that chaperone domain BRICHOS interfere with nucleation process Aβ42. Here, we explore mechanism inhibition lung surfactant protein (proSP-C) against α-Syn formation. We determine 3D NMR structure an inactive...
Photo-CIDNP is one among different promising techniques to improve nuclear magnetic resonance (NMR) sensitivity. Being sensitive particular amino acids makes it a candidate with respect biological NMR. Our goal exploit new sensitizers and compare them the present working horses flavin mononucleotide, bipyridyl, recently applied fluorescein. Among investigated dyes, we found very efficient one, Atto Thio 12, conveniently used in fluorescence microscopy 2-3 fold enhanced polarization when...
Fragment-based drug discovery has emerged as a powerful approach for developing therapeutics against challenging targets, including the GTPase KRAS. Here, we report an NMR-based screening campaign employing state-of-the-art techniques to evaluate library of 890 fragments oncogenic KRAS G12V mutant bound GMP-PNP. Further HSQC titration experiments identified hits with low millimolar affinities binding within SI/SII switch region, which forms interface effector proteins. To elucidate modes,...
The <italic>N</italic>MR<sup>2</sup> method can derive protein–fragment structures with a cooperative assignment strategy, opening an avenue for NMR-based fragment lead discovery.
Abstract. Sensitivity being one of the main hurdles nuclear magnetic resonance (NMR) can be gained by polarization techniques including chemically induced dynamic (CIDNP). Kaptein demonstrated that basic mechanism CIDNP arises from spin sorting based on coherent electron–electron dynamics during formation and recombination a radical pair in field. In photo-CIDNP interest here is between dye molecule to polarized. Here, we explore continuous-wave (CW) (denoted CW-photo-CIDNP) with set 10...
Benchtop NMR is becoming an increasingly important tool, sometimes providing a simple and low-cost alternative to high-field NMR. The Achille’s heel of even more critically benchtop its limited sensitivity. However, when combined with hyperpolarization techniques, the sensitivity boost can provide excellent that make compatible affinity studies for drug discovery. Hyperpolarization by dissolution dynamic nuclear polarization (dDNP) provides route enhancing 13C magnetic resonance (NMR) than...
Abstract. Recent advances in NMR fragment screening use sample illumination to boost sensitivity, reduce measurement time a few seconds, and concentration micromolars. Nevertheless, the absence of fully automated solution measure several hundreds samples with photoinduced hyperpolarization limits large-scale applicability method. We present setup couple an optical fiber cryogenic probe using flow-cell accessory port. This is compatible commercially available autosamplers, enabling per day.
Recent advances in NMR fragment screening use sample illumination to boost sensitivity, reduce measurement time a few seconds, and concentration micromolars. Nevertheless, the absence of fully automated solution measure several hundreds samples with photoinduced hyperpolarization limits large-scale applicability method. We present setup couple an optical fiber cryogenic probe using flow-cell accessory port. This is compatible commercially available autosamplers, enabling per day.
Abstract Nuclear magnetic resonance (NMR) is recognized as the gold standard method in fragment‐based drug design for screening, hit validation, and affinity determination. However, its deployment at a large scale limited by cost expertise needed to implement NMR routine discovery method. The increase adoption of created need biophysics provide high‐quality data weak ligand‐target interactions that can be implemented scale. must adapt position operations enter this new era. recent...
Protein-fragment complex structures are particularly sought after in medicinal chemistry to rationally design lead molecules. These usually derived using X-ray crystallography, but the failure rate is non-neglectable. NMR a possible alternative for calculation of weakly interacting complexes. Nevertheless, time-consuming protein signal assignment step remains barrier its routine application. Molecular Replacement (NMR2) versatile and rapid method that enables elucidation protein-ligand...
Structure-based drug discovery (SBDD) largely relies on structural information from X-ray crystallography because traditional NMR structure calculation methods are too time consuming to be aligned with typical timelines. The recently developed molecular replacement (NMR2) method dramatically reduces the needed generate ligand–protein complex structures using published (apo or holo) of target protein and treating all observed NOEs as ambiguous restraints, bypassing laborious process obtaining...
Abstract Fragmentbasiertes Wirkstoffdesign ist eine gut etablierte Strategie für rationales Arzneimitteldesign, wobei die Kernspinresonanzspektroskopie (NMR) auf Hochfeldspektrometern als Referenzmethode das Screening und Hit‐Validierung dient. Hochfeld‐NMR‐Spektrometer sind jedoch nicht nur teuer, sondern erfordern auch spezielle Wartung, einen speziellen Raum Kühlung mit flüssigem Helium angewiesen, was angesichts der wiederkehrenden weltweiten Heliumknappheit kritisch geworden ist. Wir...
Figüre S1: CAD drawing of a Brüker CryoProbe
Benchtop NMR is becoming an increasingly important tool, sometimes providing a simple and low-cost alternative to high-field NMR. The Achille’s heel of even more critically benchtop its limited sensitivity. However, when combined with hyperpolarization techniques, the sensitivity boost can provide excellent that make compatible affinity studies for drug discovery. Hyperpolarization by dissolution dynamic nuclear polarization (dDNP) provides route enhancing 13C magnetic resonance (NMR) than...
Several 5,6-dialkyl-2,4-diarylpyrimidines were prepared and their electron ionization (EI) mass spectra reported. The benzylic cleavage takes place easily together with an important McLafferty rearrangement. involvement of the nitrogen atom appears to be in fragmentation 5-methyl-substituted pyrimidines. In contrast, 6-methyl-substituted pyrimidines undergo without hydrogen transfer. Thus, difference spectrometric behaviour allows identification these isomeric compounds which, exhibit only...
Exact nuclear Overhauser enhancement (eNOE) yields highly accurate, ensemble averaged 1H-1H distance restraints with an accuracy of up to 0.1 Å for the multi-state structure determination proteins as well magnetic resonance molecular replacement (NMR2) determine protein-ligand interaction site in a time-efficient manner. However, latter application, acquired eNOEs lack obtainable precision because asymmetrical nature filtered spectroscopy (NOESY) experiment used NMR2. This error is further...
Summary The viral life cycle usurps host cellular factors, redirecting them from physiological functions to needs thereby revealing their “moonlighting” functions, disturbing proteostasis, and increasing risk of specific, virus-associated protein misfolding diseases (PMD). Identifying such virus-repurposed proteins therefore allow study fundamental events leading associated “sporadic” PMD. Here, we identified a small molecule with unprecedented activity against neurotropic herpes simplex...