7196 research outputs found
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Linking solid-state phenomena via energy differences in `archetype crystal structures'.
No full textCategorization underlies understanding. Conceptualizing solid-state structures of organic molecules with `archetype crystal structures' bridges established categories of disorder, polymorphism and solid solutions and is herein extended to special position and high-Z' structures. The concept was developed in the context of disorder modelling [Dittrich, B. (2021). IUCrJ, 8, 305-318] and relies on adding quantum chemical energy differences between disorder components to other criteria as an explanation as to why disorder - and disappearing disorder - occurs in an average structure. Part of the concept is that disorder, as probed by diffraction, affects entire molecules, rather than just the parts of a molecule with differing conformations, and the finding that an R·T energy difference between disorder archetypes is usually not exceeded. An illustrative example combining disorder and special positions is the crystal structure of oestradiol hemihydrate analysed here, where its space-group/subgroup relationship is required to explain its disorder of hydrogen-bonded hydrogen atoms. In addition, we show how high-Z' structures can also be analysed energetically and understood via archetypes: high-Z' structures occur when an energy gain from combining different rather than overall alike conformations in a crystal significantly exceeds R·T, and this finding is discussed in the context of earlier explanations in the literature. Twinning is not related to archetype structures since it involves macroscopic domains of the same crystal structure. Archetype crystal structures are distinguished from crystal structure prediction trial structures in that an experimental reference structure is required for them. Categorization into archetype structures also has practical relevance, leading to a new practice of disorder modelling in experimental least-squares refinement alluded to in the above-mentioned publication
Viscosity reduction and stabilization of highly concentrated monoclonal antibody solutions with proline analogues
No full textInvestigation of several compounds based on Proline with a focu on their viscosity reducing effects. We aim to research the mechanism of viscosity reduction of mAb solutions using small molecule excipients and find new, nontoxic viscosity reducers with stabilizing effect on the model mAb. If successful, discovery of effective viscosity reducers will facilitate the development of mAb formulations for subcutaneous administration and contribute to an approachable and sustainable treatment with biological medicines. Lastly, molecular dynamics simulations have been performed to evaluate the suitability of such methods in predicting viscosity reducing effects
Advancing drug discovery through assay development: a survey of tool compounds within the human solute carrier superfamily
No full textWith over 450 genes, solute carriers (SLCs) constitute the largest transporter
superfamily responsible for the uptake and efflux of nutrients, metabolites, and
xenobiotics in human cells. SLCs are associated with a wide variety of human
diseases, including cancer, diabetes, and metabolic and neurological disorders.
They represent an important therapeutic target class that remains only partly
exploited as therapeutics that target SLCs are scarce. Additionally, many small
molecules reported in the literature to target SLCs are poorly characterized. Both
features may be due to the difficulty of developing SLC transport assays that fulfill
the quality criteria for high-throughput screening. Here, we report one of the
main limitations hampering assay development within the RESOLUTE
consortium: the lack of a resource providing high-quality information on SLC
tool compounds. To address this, we provide a systematic annotation of tool
compounds targeting SLCs. We first provide an overview on RESOLUTE assays.
Next, we present a list of SLC-targeting compounds collected from the literature
and public databases; we found that most data sources lacked specificity data.
Finally, we report on experimental tests of 19 selected compounds against a panel
of 13 SLCs from seven different families. Except for a few inhibitors, which were active on unrelated SLCs, the tested inhibitors demonstrated high selectivity for
their reported targets. To make this knowledge easily accessible to the scientific
community, we created an interactive dashboard displaying the collected data in
the RESOLUTE web portal (https://re-solute.eu). We anticipate that our openaccess
resources on assays and compounds will support the development of future
drug discovery campaigns for SLCs
EBF project: promoting replacement of preclinical matrix for IGM assays
No full textWe have generated some data for the EBF (The European Bioanalysis Forum) project - an experiment to check the use of surrogate matrix for non-clinical assay set up and sample analysis for biotherapeutics (mAbs, therapeutic proteins). The goal is to evaluate for which assay types (ELISA, MSD, others, also different assay formats like free and total PK) the specific animal matrix could be substituted by a more abundant surrogate matrix, e.g. horse serum. This strategy would supports 3R implementation.
In this experiment we used Novartis compound (only nick name will be shared, not NVS code) and we would also share some general description of bioanalytical assay
Manganese(I)-Catalyzed Functionalization of Tryptophan on Water
No full textThe manganese(I)-catalyzed allylation of the amino acid tryptophan was realized under mild conditions using water as a sustainable and nonhazardous reaction medium instead of classical organic solvents. Synthetically useful α,β-unsaturated esters could be accessed by reaction with Morita-Baylis-Hillman (MBH) adducts following a direct C‒H activation approach. The robustness of this procedure was reflected by kinetic analysis at different reaction temperatures and reduced catalyst loadings
Nonclassical Zwitterions as a Design Principle to Reduce Lipophilicity without Impacting Permeability.
No full textThe ionization of bioactive molecules impacts many ADME-relevant physicochemical properties, in particular, solubility, lipophilicity, and permeability. Ampholytes contain both acidic and basic groups and are distinguished as ordinary ampholytes and zwitterions. An influential review states that zwitterions only exist if the acidic pKa is significantly lower than the basic pKa. Through concordance of measured and calculated pKa and log P, we show that the zwitterionic behavior of several marketed drugs and natural products occurs despite a low or negative ΔpKa. These nonclassical zwitterions are characterized by a weak acidic and basic pKa and conjugation through an extended aromatic system, often including pseudorings via intramolecular hydrogen bonds. In contrast to most classical zwitterions, nonclassical zwitterions can exhibit excellent permeability. As permeability and lipophilicity are typically correlated, the combination of low lipophilicity and high permeability makes nonclassical zwitterions an attractive design principle in medicinal chemistry
A stub a day keeps the docstrings at bay
No full textThis blog post expands a bit on the topic I presented last year in Mainz during a lightning talk at the 2023 RDKit UGM, i.e., the generation of RDKit stubs and programmatic patching of existing Python docstrings
Pain-Phenotyping in Osteoarthritis: Current Concepts, Evidence, and Considerations towards a Comprehensive Framework for Assessment and Treatment
No full textObjectives
Pain as central symptom of osteoarthritis (OA) needs to be addressed as part of successful treatment. The assessment of pain as feature of disease or outcome in clinical practice and drug development remains a challenge due to its multidimensionality and the plethora of confounders. This article aims at providing insights into our understanding of OA pain-phenotypes and suggests a framework for systematic and comprehensive assessments.
Methods
This narrative review is based on a search of current literature for various combinations of the search terms “pain-phenotype” and “knee OA” and summarizes current knowledge on OA pain-phenotypes, putting OA pain and its assessment into perspective of current research efforts.
Results
Pain is a complex phenomenon, not necessarily associated with tissue damage. Various pain-phenotypes have been described in knee OA. Among those, a phenotype with high pain levels not necessarily matching structural changes and a phenotype with low pain levels and impact are relatively consistent. Further subgroups can be differentiated based on patient reported outcome measures, assessments of comorbidities, anxiety and depression, sleep, activity and objective measures such as quantitative sensory testing.
Conclusions
The complexity of both OA as disease and pain in OA prompt the definition of a set of variables that facilitate assessments comparable across studies to maximize our understanding of pain, as central concern for the patient
Letters or Not, Here We Come! A Communal Perspective on Credentials Needed for a Productive Career in Veterinary Pathology
No full textVeterinary pathology credentials serve as a concise means attesting to educational attainments and experiences indicating a readiness for professional practice. Given the cost, time and stress associated with obtaining credentials, pathologists must consider what credentials enhance their readiness. In this commentary, the authors describe how their various degrees and certifications have facilitated their success. The minimum credentials for veterinary pathology practice are a veterinary medical degree (DVM or equivalent) and advanced pathology training (residency and/or on-the-job “apprenticeship”) ideally culminating in board certification in pathology (ACVP or equivalent). Graduate degrees (MS, PhD, MPH, etc.) and/or other qualifications in allied fields (laboratory animal medicine, poultry medicine or internal medicine, toxicology boards) may improve employability by affirming specialty knowledge in an allied discipline. The authors note that pathology positions may be obtained without a long list of letters; that more credentials may provide occupational flexibility for some employers; and that a good work ethic, experience in the field, abilitye to adapt to changes, job satisfaction, and demonstrated productivity are also important criteria for career success as a veterinary pathologist
In-vivo screening implicates endoribonuclease Regnase-1 in modulating senescence-associated lysosomal changes.
No full textAccumulation of senescent cells accelerates aging and age-related diseases, whereas preventing this accumulation extends the lifespan in mice. A characteristic of senescent cells is increased staining with β-galactosidase (β-gal) ex vivo. Here, we describe a progressive accumulation of β-gal staining in the model organism C. elegans during aging. We show that distinct pharmacological and genetic interventions targeting the mitochondria and the mTORC1 to the nuclear core complex axis, the non-canonical apoptotic, and lysosomal-autophagy pathways slow the age-dependent accumulation of β-gal. We identify a novel gene, rege-1/Regnase-1/ZC3H12A/MCPIP1, modulating β-gal staining via the transcription factor ets-4/SPDEF. We demonstrate that knocking down Regnase-1 in human cell culture prevents senescence-associated β-gal accumulation. Our data provide a screening pipeline to identify genes and drugs modulating senescence-associated lysosomal phenotypes