| 1. |
- Bondarev, Andrey D., et al.
(författare)
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Opportunities and challenges for drug discovery in modulating Adhesion G protein-coupled receptor (GPCR) functions
- 2020
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Ingår i: Expert Opinion on Drug Discovery. - : TAYLOR & FRANCIS LTD. - 1746-0441 .- 1746-045X. ; 15:11, s. 1291-1307
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Forskningsöversikt (refereegranskat)abstract
- Introduction: The G protein-coupled receptors (GPCR) superfamily is among the most widely exploited targets for therapeutics, with drugs mainly targeting the Rhodopsin, Glutamate and Secretin family receptors. The receptors of the Adhesion family, however, remain comparatively unexplored in this aspect. This review aims to discuss the druggability of Adhesion GPCRs (aGPCR), highlighting the relevant opportunities and challenges.Areas Covered: In this review, the authors provide a disease-oriented summary of aGPCR involvement in humans and discuss the current status of characterizing therapeutic agents with a focus on new opportunities using low molecular weight substances.Expert opinion: The small molecule antagonist dihydromunduletone and partial agonist 3-alpha-acetoxydihydrodeoxygedunin, along with the endogenous natural ligand synaptamide currently comprise some of the most important discoveries made in an attempt to characterize aGPCR druggability. The small molecule modulators provide important insights regarding the structure-activity relationship and suggest that targeting the tethered peptide agonist results in a nonselective pharmacological action, while synaptamide may be considered a potentially attractive tool to achieve a higher degree of selectivity.
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| 2. |
- Bondarev, Andrey D, et al.
(författare)
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Recent developments of HDAC inhibitors : Emerging indications and novel molecules
- 2021
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Ingår i: British Journal of Clinical Pharmacology. - : John Wiley & Sons. - 0306-5251 .- 1365-2125. ; 87:12, s. 4577-4597
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Tidskriftsartikel (refereegranskat)abstract
- The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a high number of clinical trials involving HDAC inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 32 agents with HDAC-inhibiting properties, of which 29 were found to interact with the HDAC enzymes as their primary therapeutic target. In this review, we provide an overview of the clinical drug development highlighting the recent advances and provide analysis of specific trials and, where applicable, chemical structures. We found haematologic neoplasms continue to represent the majority of clinical indications for this class of drugs; however, it is clear that there is an ongoing trend towards diversification. Therapies for non-oncology indications including HIV infection, muscular dystrophies, inflammatory diseases as well as neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia and Friedreich's ataxia are achieving promising clinical progress. Combinatory regimens are proving to be useful to improve responsiveness among FDA-approved agents; however, it often results in increased treatment-related toxicities. This analysis suggests that the indication field is broadening through a high number of clinical trials while several fields of preclinical development are also promising.
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| 3. |
- Bondarev, Andrey D., et al.
(författare)
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Recent developments of phosphodiesterase inhibitors : Clinical trials, emerging indications and novel molecules
- 2022
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 13
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Forskningsöversikt (refereegranskat)abstract
- The phosphodiesterase (PDE) enzymes, key regulator of the cyclic nucleotide signal transduction system, are long-established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a particularly high number of clinical trials involving PDE inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 87 agents with PDE-inhibiting capacity, of which 85 interact with PDE enzymes as primary target. We provide an overview of the clinical drug development with focus on the current clinical uses, novel molecules and indications, highlighting relevant clinical studies. We found that the bulk of current clinical uses for this class of therapeutic agents are chronic obstructive pulmonary disease (COPD), vascular and cardiovascular disorders and inflammatory skin conditions. In COPD, particularly, PDE inhibitors are characterised by the compliance-limiting adverse reactions. We discuss efforts directed to appropriately adjusting the dose regimens and conducting structure-activity relationship studies to determine the effect of structural features on safety profile. The ongoing development predominantly concentrates on central nervous system diseases, such as schizophrenia, Alzheimer's disease, Parkinson's disease and fragile X syndrome; notable advancements are being also made in mycobacterial infections, HIV and Duchenne muscular dystrophy. Our analysis predicts the diversification of PDE inhibitors' will continue to grow thanks to the molecules in preclinical development and the ongoing research involving drugs in clinical development.
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| 4. |
- Martin, Tina, et al.
(författare)
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SIP laboratory data: frequency-domain versus time-domain
- 2021
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Spectral information from induced polarisation (IP) measurements can be used for several applications as the characterisation of the lithology, the estimation of hydraulic parameters, the localization of contaminated areas and many more.So far, the spectral content has been mainly determined in frequency domain (FD). Due to significant instrumental developments and advanced data processing and inversion tools, it is nowadays also possible to extract spectral information from time-domain (TD) measurements. Even though the results from both domains should be theoretically identical, differences can be observed in the practical application. To compare both domains, we started with numerical models and measurements at test circuits. Thereafter, we conducted measurements on different types of well-known material (e.g., sandstones and wood samples) in a controlled laboratory environment. For the TDIP measurements, the AIE-2 instrument was used and the FDIP spectra were recorded with the SIP Fuchs III device. Besides the measurement results, shown as decay curves in TD and amplitude and phase spectra in FD, also the Differential Polarisation parameter (DP) is presented. This parameter is calculated from the TD decay curve and proves to be well correlated with the phase in FD. The comparison of DP and phase curves enables a first visual check and a discrimination between different samples. To compare both domains qualitatively, the relaxation time distribution (RTD) was calculated for all data. Theresults are in (partly very) good agreement between both domains, depending on the data quality. We found that the RTDs are in better agreement for the wood samples than for the sandstone samples. We attribute the differences to the lower data quality of the TD measurements of sandstones, which were performed with lower current in comparison to the wood samples. Therefore, the TD decay curves at later times are more affected by noise.
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| 5. |
- Martin, Tina, et al.
(författare)
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Spectral induced polarization: frequency domain versus time domain laboratory data
- 2021
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Ingår i: Geophysical Journal International. - : Oxford University Press (OUP). - 0956-540X .- 1365-246X. ; 225, s. 1982-2000
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Tidskriftsartikel (refereegranskat)abstract
- Spectral information obtained from induced polarization (IP) measurements can be used in a variety of applications and is often gathered in frequency domain (FD) at the laboratory scale. In contrast, field IP measurements are mostly done in time domain (TD). Theoretically, the spectral content from both domains should be similar. In practice, they are often different, mainly due to instrumental restrictions as well as the limited time and frequency range ofmeasurements. Therefore, a possibility of transition between both domains, in particular for the comparison of laboratory FD IP data and field TD IP results, would be very favourable. To compare both domains, we conducted laboratory IP experiments in both TD and FD.We started with three numerical models and measurements at a test circuit, followed by several investigations for different wood and sandstone samples. Our results demonstrate that the differential polarizability (DP), which is calculated from the TD decay curves, can be compared very well with the phase of the complex electrical resistivity. Thus, DP can be used for a first visual comparison of FD and TD data, which also enables a fast discriminationbetween different samples. Furthermore, to compare both domains qualitatively, we calculated the relaxation time distribution (RTD) for all data. The results are mostly in agreement between both domains, however, depending on the TD data quality. It is striking that the DP and RTD results are in better agreement for higher data quality in TD. Nevertheless, we demonstrate that IP laboratory measurements can be carried out in both TD and FD with almost equivalentresults. The RTD enables a good comparability of FD IP laboratory data with TD IP field data.
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| 6. |
- Tarasov, Dmitry, et al.
(författare)
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AqSO biorefinery : a green and parameter-controlled process for the production of lignin-carbohydrate hybrid materials
- 2022
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Ingår i: Green Chemistry. - : Royal Society of Chemistry (RSC). - 1463-9262 .- 1463-9270. ; 24:17, s. 6639-6656
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Tidskriftsartikel (refereegranskat)abstract
- The current biorefineries are focused on the comprehensive fractionation of biomass components into separate lignin and carbohydrate fractions for the production of materials, platform chemicals and biofuel. However, it has become obvious that the combination of lignin and carbohydrates can have significant technical, environmental, and economic benefits as opposed to their separate use. Herein, we developed a green, simple, and flexible biorefinery concept for the integrated utilization of all major biomass components for high-value applications with the focus on functional lignin–carbohydrate hybrids (LCHs). The established process consisted of a modified hydrothermal treatment (HTT) of birch wood followed by solvent extraction of the resulting solids and is therefore named AquaSolv Omni (AqSO) biorefinery. The AqSO biorefinery produces three major streams: hydrolysate (hemicellulose-derived products), solvent-extracted lignin–carbohydrate complexes (LCCs) and cellulose-rich fibers. Specific process conditions were found to facilitate the production of LCCs of different types in high yields as a new valuable and industrially realistic process stream. The effect of the process severity and liquid to solid (L/S) ratio on the yields and compositions of the produced fractions as well as on the structure and properties of the extracted LCCs was investigated using state of the art NMR spectroscopy and molar mass distribution analysis among other methods. The high flexibility of the process allows for engineering of the resulting products in a wide range of chemical compositions, structures and physicochemical properties and therefore gives a good opportunity to optimize the products for specific high-value applications. The process can be easily combined with other biorefinery operations (e.g., enzymatic hydrolysis, pulping, bleaching) to be incorporated into existing value chains or create new ones and thus is suitable for different biorefinery scenarios. First examples of high-value applications of AqSO biorefinery LCHs are reported. LCC nanoparticles (LCCNPs) were produced for the first time directly from the solvent extract and their properties were investigated. LCCNPs could efficiently stabilize Pickering emulsions of tetrahydrofurfuryl methacrylate and allowed their free radical polymerization. In addition, AqSO LCHs showed promising results as wood adhesives. Overall, our results provide detailed information on the complex lignocellulosic fractions and bridge the gap from process engineering to sustainable product development.
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| 7. |
- Trunschke, Annette, et al.
(författare)
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Towards Experimental Handbooks in Catalysis
- 2020
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Ingår i: Topics in Catalysis. - : Springer Science and Business Media LLC. - 1572-9028 .- 1022-5528. ; 63:19-20, s. 1683-1699
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Tidskriftsartikel (refereegranskat)abstract
- The “Seven Pillars” of oxidation catalysis proposed by Robert K. Grasselli represent an early example of phenomenological descriptors in the field of heterogeneous catalysis. Major advances in the theoretical description of catalytic reactions have been achieved in recent years and new catalysts are predicted today by using computational methods. To tackle the immense complexity of high-performance systems in reactions where selectivity is a major issue, analysis of scientific data by artificial intelligence and data science provides new opportunities for achieving improved understanding. Modern data analytics require data of highest quality and sufficient diversity. Existing data, however, frequently do not comply with these constraints. Therefore, new concepts of data generation and management are needed. Herein we present a basic approach in defining best practice procedures of measuring consistent data sets in heterogeneous catalysis using “handbooks”. Selective oxidation of short-chain alkanes over mixed metal oxide catalysts was selected as an example.
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