A5081491553- Crystallization and Solubility Studies
- HIV/AIDS drug development and treatment
- Chemical Synthesis and Analysis
- X-ray Diffraction in Crystallography
- Hepatitis C virus research
- Click Chemistry and Applications
- Computational Drug Discovery Methods
- NMR spectroscopy and applications
- Analytical Chemistry and Chromatography
- Peptidase Inhibition and Analysis
- Insect Pest Control Strategies
- Crystallography and molecular interactions
- Biosimilars and Bioanalytical Methods
- Protein Degradation and Inhibitors
- Metabolomics and Mass Spectrometry Studies
- Natural product bioactivities and synthesis
- Protein Structure and Dynamics
- Mycobacterium research and diagnosis
- DNA and Nucleic Acid Chemistry
- Bioactive natural compounds
- Mass Spectrometry Techniques and Applications
- Synthesis and Biological Activity
- Synthesis and Catalytic Reactions
- Bioactive Natural Diterpenoids Research
- Tuberculosis Research and Epidemiology
Uppsala University
2020-2024
Max-Planck-Institut für Kohlenforschung
2024
University of Dundee
2024
University of Groningen
2019
Dialyse Centrum Groningen
2019
It has been hypothesised that drugs in the chemical space "beyond rule of 5" (bRo5) must behave as molecular chameleons to combine otherwise conflicting properties, including aqueous solubility, cell permeability and target binding. Evidence for this has, however, limited cyclic peptide cyclosporine A. Herein, we show non-peptidic macrocyclic roxithromycin, telithromycin spiramycin chameleons, with rifampicin showing a less pronounced behaviour. In particular display marked, yet flexibility...
Halenium ions, X+, are particularly strong halogen-bond donors that interact with two Lewis bases simultaneously to form linear [D···X···D]+-type halonium complexes. Their three-center, four-electron halogen bond is both fundamentally interesting and technologically valuable as it tames the reactivity of halogen(I) opening up new horizons in a variety fields including synthetic organic supramolecular chemistry. Understanding this bonding situation enables development improved transfer...
It was recognized only recently that the sister norcembranoids scabrolides A and B have notably different carbotricyclic scaffolds. Therefore, our synthesis route leading to scabrolide could not be extended its sibling. Rather, a conceptually new approach had devised relied on challenging intramolecular alkenylation of ketone forge congested central cycloheptene ring at bridgehead enone site; required cyclization precursor attained by lanthanide-catalyzed Mukaiyama–Michael addition. The...
Macrocycles constitute superior ligands for targets that have flat binding sites but often require long synthetic routes, emphasizing the need property prediction prior to synthesis. We investigated scope and limitations of machine learning classification models regression predicting cell permeability a set denovo-designed, drug-like macrocycles. 2D-Based models, which are fast calculate, discriminated between macrocycles had low-medium high may be used as virtual filters in early drug...
Paritaprevir is an orally bioavailable, macrocyclic drug used for treating chronic Hepatitis C virus (HCV) infection. Its structures have been elusive to the public until recently when one of crystal forms solved by microcrystal electron diffraction (MicroED). In this work, MicroED two distinct polymorphic paritaprevir are reported from same experiment. The different polymorphs show conformational changes in core, as well cyclopropyl sulfonamide and methyl pyrazinamide substituents....
Higher-order foldamers represent a unique class of supramolecules at the forefront molecular design. Herein we control quaternary folding using novel approach that combines halogen bonding (XBing) and hydrogen (HBing). We present first anion-templated double helices induced by bonds (XBs) stabilized "hydrogen bond enhanced bonds" (HBeXBs). Our findings demonstrate number orientation (HB) XB donors significantly affect structure guest selectivity two similar oligomers. This research offers...
Abstract The nuclear magnetic resonance extracted data (NMReDATA) format has been proposed as a way to store, exchange, and disseminate (NMR) physical chemical metadata of compounds. In this paper, we report on analytical workflows that take advantage the uniform standardized NMReDATA format. We also give access repository sample data, which can serve for validating software packages encode or decode files in
Macrocycles are important drug leads with many advantages including the ability to target flat and featureless binding sites as well act molecular chameleons thereby reach intracellular targets. However, due their complex structures inherent flexibility, macrocycles difficult study structurally, there limited structural data available. Herein, we use cryo-EM method MicroED determine novel atomic of several that have previously resisted determination. We show similar complexity can now be...
The ability to adjust conformations in response the polarity of environment, i.e. molecular chameleonicity, is considered be important for conferring both high aqueous solubility and cell permeability drugs chemical space beyond Lipinski's rule 5. We determined conformational ensembles populated by antiviral asunaprevir, simeprevir, atazanavir daclatasvir polar (DMSO-d6 ) non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas first three showed large...
Abstract Cystobactamids are aromatic oligoamides that exert their natural antibacterial properties by inhibition of bacterial gyrases. Such were proposed to inhibit α‐helix‐mediated protein‐protein interactions and may serve for specific recognition DNA. Based on this suggestion, we designed new derivatives have duplicated cystobactamid triarene units as model systems decipher the binding mode cystobactamids double stranded Solution NMR analyses revealed well elongated analogues show an...
Three new (1–3) and six known rotenoids (5–10), along with three isoflavones (11–13), were isolated from the leaves of Millettia oblata ssp. teitensis. A glycosylated isoflavone (4), four (14–18), one chalcone (19) root wood extract same plant. The structures elucidated by NMR mass spectrometric analyses. absolute configuration chiral compounds was established a comparison experimental ECD VCD data those calculated for possible stereoisomers. This is first report on use to assign rotenoids....
Three new dihydroflavonols, gloverinols A-C (
Chemical probes that label proteins of interest in the context complex biological samples are useful research tools. The reactive group forms covalent bond with target protein has a large effect on selectivity and selecting appropriate determines success probe. We here report development combinatorial methodology based imine chemistry enables straightforward situ synthesis screening different groups thereby simplifies identification probe leads. Using our methodology, we found chemical...
Cyclisation of peptides by forming thioether (lanthionine), disulfide (cystine) or methylene thioacetal bridges between side chains is established as an important tool to stabilise a given structure, enhance metabolic stability and optimise both potency selectivity. However, systematic comparative study the effects differing bridging modalities on peptide conformation has not previously been carried out. In this paper, we have used NMR deconvolution algorithm, NAMFIS, determine...
Six new crotofolane diterpenoids (1–6) and 13 known compounds (7–19) were isolated from the MeOH–CH2Cl2 (1:1, v/v) extracts of leaves stem bark Croton kilwae. The structures elucidated by extensive analysis spectroscopic mass spectrometric data. structure crotokilwaepoxide A (1) was confirmed single-crystal X-ray diffraction, allowing for determination its absolute configuration. crude investigated antiviral activity against respiratory syncytial virus (RSV) human rhinovirus type-2 (HRV-2)...
The discovery of cell permeable and orally bioavailable von Hippel-Lindau (VHL) proteolysis targeting chimeras (PROTACs) is challenging as their structures locates them at, or beyond, the outer limits oral druggable space. We have designed a set nine VHL PROTACs found that linker had profound impact on passive permeability. Determination solution ensembles in nonpolar solvent revealed high permeability was correlated to ability adopt folded conformations low accessible 3D polar surface area....
Abstract To date, most nuclear magnetic resonance (NMR)‐based 3‐D structure determinations of both small molecules and biopolymers utilize the Overhauser effect (NOE) via NOESY spectra. The acquisition high‐quality spectra is a prerequisite for quantitative analysis providing accurate interatomic distances. As NOE build‐ups time‐consuming, acceleration process by use non‐uniform sampling (NUS) may seem beneficial; however, quantitativity acquired with NUS has not yet been validated. Herein,...
Paritaprevir is an orally bioavailable, macrocyclic drug used for treating chronic Hepatitis C virus infection. Its structures had been elusive to the public until recently when one of crystal forms was solved by MicroED. In this work, we report MicroED two distinct polymorphic paritaprevir from same experiment. The different polymorphs show conformational changes in core, as well cyclopropylsulfonamide and methylpyrazinamide substituents. Molecular docking shows that conformations fits into...
Carbapenem resistance caused by metallo-β-lactamases is a serious global challenge that, if not tackled efficiently, expected to lead millions of deaths in the coming decades. Verona-integron encoded metallo-β-lactamase 2 (VIM-2) bacterial enzyme that has been reported from multidrug-resistant nosocomial isolates Pseudomonas aeruginosa and other Gram-negative pathogens. As it hydrolyzes most β-lactams including carbapenems, major threat current antimicrobial chemotherapies. So far, there no...
Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that induce ubiquitination and degradation of a target protein via recruitment to an E3 ligase. The linker influences many steps the PROTAC mode action, from cellular permeability ternary complex formation degradation. Much interest has therefore been devoted design fine-tune molecular mechanistic properties PROTACs. In this study, we present FerroTACs, novel strategy incorporating ferrocene as chemotype. We exemplify...
Macrocyclic Drug Structures by MicroED Microcrystal electron diffraction (MicroED) is applied to capture two polymorphic structures of the elusive and flexible macrocyclic drug paritaprevir, which used for treating chronic Hepatitis C virus (HCV) infection. Its potential interaction with target HCV non-structural 3/4A serine protease investigated molecular docking. More details can be found in article number 2300570 Tamir Gonen co-workers.