| 1. |
- Kuhn, Stefan, et al.
(författare)
-
NMReDATA : Tools and applications
- 2021
-
Ingår i: Magnetic Resonance in Chemistry. - : John Wiley & Sons. - 0749-1581 .- 1097-458X. ; 59:8, s. 792-803
-
Tidskriftsartikel (refereegranskat)abstract
- The nuclear magn etic resonance extracted data (NMReDATA) format has beenproposed as a way to store, exchange, and disseminate nuclear magneticresonance (NMR) data and physical and chemical metadata of chemical com-pounds. In this paper, we report on analytical workflows that take advantageof the uniform and standardized NMReDATA format. We also give access to arepository of sample data, which can serve for validating software packagesthat encode or decode files in NMReDATA format.
|
|
| 2. |
- Danelius, Emma, et al.
(författare)
-
MicroED as a Powerful Tool for Structure Determination of Macrocyclic Drug Compounds Directly from Their Powder Formulations
- 2023
-
Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 18:12, s. 2582-2589
-
Tidskriftsartikel (refereegranskat)abstract
- Macrocycles are important drug leads with many advantages including the ability to target flat and featureless binding sites as well as to act as molecular chameleons and thereby reach intracellular targets. However, due to their complex structures and inherent flexibility, macrocycles are difficult to study structurally, and there are limited structural data available. Herein, we use the cryo-EM method MicroED to determine the novel atomic structures of several macrocycles that have previously resisted structural determination. We show that structures of similar complexity can now be obtained rapidly from nanograms of material and that different conformations of flexible compounds can be derived from the same experiment. These results will have an impact on contemporary drug discovery as well as natural product exploration.
|
|
| 3. |
- Danelius, Emma, et al.
(författare)
-
Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs
- 2020
-
Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 26:23, s. 5231-5244
-
Tidskriftsartikel (refereegranskat)abstract
- It has been hypothesised that drugs in the chemical space "beyond the 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, been limited to the cyclic peptide cyclosporine A. Herein, we show that the non-peptidic and macrocyclic drugs roxithromycin, telithromycin and spiramycin behave as molecular chameleons, with rifampicin showing a less pronounced behaviour. In particular roxithromycin, telithromycin and spiramycin display a marked, yet limited flexibility and populate significantly less polar and more compact conformational ensembles in an apolar than in a polar environment. In addition to balancing of membrane permeability and aqueous solubility, this flexibility also allows binding to targets that vary in structure between species. The drugs' passive cell permeability correlates to their 3D polar surface area and corroborate two theoretical models for permeability, developed for cyclic peptides. We conclude that molecular chameleonicity should be incorporated in the design of orally administered drugs in the bRo5 space.
|
|
| 4. |
- Wieske, Lianne H. E., 1994-, et al.
(författare)
-
Ensemble determination by NMR data deconvolution
- 2023
-
Ingår i: Nature Reviews Chemistry. - : Springer Nature. - 2397-3358. ; 7, s. 511-524
-
Forskningsöversikt (refereegranskat)abstract
- Nuclear magnetic resonance (NMR) is the spectroscopic technique of choice for determining molecular conformations in solution at atomic resolution. As solution NMR spectra are rich in structural and dynamic information, the way in which the data should be acquired and handled to deliver accurate ensembles is not trivial. This Review provides a guide to the NMR experiment selection and parametrization process, the generation of viable theoretical conformer pools and the deconvolution of time-averaged NMR data into a conformer ensemble that accurately represents a flexible molecule in solution. In addition to reviewing the key elements of solution ensemble determination of flexible mid-sized molecules, the feasibility and pitfalls of data deconvolution are discussed with a comparison of the performance of representative algorithms.
|
|
| 5. |
- Wieske, Lianne H. E., 1994-, et al.
(författare)
-
Going Viral : An Investigation into the Chameleonic Behaviour of Antiviral Compounds
- 2023
-
Ingår i: Chemistry - A European Journal. - : Wiley-VCH Verlagsgesellschaft. - 0947-6539 .- 1521-3765. ; 29:8
-
Tidskriftsartikel (refereegranskat)abstract
- The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d6) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as “partial molecular chameleons” and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption.
|
|
| 6. |
- Wieske, Lianne H. E., 1994-, et al.
(författare)
-
Halogen Bonds of Halogen(I) Ions : Where Are We and Where to Go?
- 2023
-
Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 146:1, s. 3-18
-
Forskningsöversikt (refereegranskat)abstract
- 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) ions, opening up new horizons in a variety of fields including synthetic organic and supramolecular chemistry. Understanding this bonding situation enables the development of improved halogen(I) transfer reactions and of advanced functional materials. Following a decade of investigations of basic principles, the range of applications is now rapidly widening. In this Perspective, we assess the status of the field and identify its key advances and the main bottlenecks. Clearing common misunderstandings that may hinder future progress, we aim to inspire and direct future research efforts.
|
|
