7196 research outputs found
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Sharing of Ames report
No full textThe raw data and structure has already been shared to the Vitic database; it is now requested to also share the reports. Both reports do not include any sensitive information but only Ames test data for a small chemical (2-Nitrobenzenesulfonyl chloride)
Chimera: Accurate retrosynthesis prediction by ensembling models with diverse inductive biases
No full textPlanning and conducting chemical syntheses remains
a major bottleneck in the discovery of functional
small molecules, and prevents fully leveraging generative
AI for molecular inverse design. While early work
has shown that ML-based retrosynthesis models can
predict reasonable routes, their low accuracy for less
frequent, yet important reactions has been pointed
out. As multi-step search algorithms are typically
limited to reactions predicted as likely by the underlying
model, the applicability of those tools is inherently
constrained by the accuracy of the retrosynthesis
prediction model. Inspired by how chemists use
different strategies to ideate reactions, we propose
Chimera: a meta-framework for building highly accurate
reaction models that combine predictions from
diverse base models with complementary inductive biases
using a learning-based ensembling strategy. We
instanstiate the framework with two newly developed
components, which themselves are state of the art in
their categories. Through experiments across several
orders of magnitude in data scale and time-splits, we
show that Chimera outperforms all major models by a
significant margin, owing both to the good individual
performance of its constituents, but also to the scalability
of our ensembling strategy. Moreover, we find
that PhD-level organic chemists significantly prefer
routes by Chimera over all tested baselines in terms of
quality. Finally, we transfer the checkpoint trained on
the largest data scale to an internal reactions dataset
of a major pharmaceutical company, showing robust
generalization under distribution shift. With the new
dimension that our meta-framework introduces, we
anticipate further acceleration in the development of
even more accurate models
CD206+macrophages are relevant non-invasive imaging biomarkers and therapeutic targets in experimental lung fibrosis
No full textBackground Interstitial lung diseases (ILDs) include a large number of diseases associated with progressive pulmonary fibrosis (PPF), including idiopathic pulmonary fibrosis (IPF). Despite the rarity of each of the fibrotic ILDs individually, they cumulatively affect a considerable number of patients. PPF is characterised by an excessive collagen deposition leading to functional decline.
Objectives Therapeutic options are limited to nintedanib and pirfenidone which are only able to reduce fibrosis progression. CD206-expressing M2 macrophages are involved in fibrosis progression, and whether they may be relevant therapeutic targets or biomarkers remains an open question.
Results In our study, CD206+ lung macrophages were monitored in bleomycin-induced lung fibrosis in mice by combining flow cytometry, scRNAseq and in vivo molecular imaging using a single photon emission computed tomography (SPECT) radiopharmaceutical, 99mTc-tilmanocept. The antifibrotic effect of the inhibition of M2 macrophage polarisation with a JAK inhibitor, tofacitinib, was assessed in vivo. We demonstrate that CD206-targeted in vivo SPECT imaging with 99mTc-tilmanocept was able to accurately detect and quantify the increase in CD206+ macrophages from early to advanced stages of experimental fibrosis and ex vivo in lung biopsies from patients with IPF. CD206-targeted imaging also specifically detected a decrease in CD206+ lung macrophages on nintedanib and tofacitinib treatment. Importantly, early in vivo imaging of CD206+ macrophages allowed the prediction of experimental lung fibrosis progression as well as nintedanib and tofacitinib efficacy.
Conclusions These findings indicate that M2 macrophages may be relevant theranostic targets for personalised medicine for patients with PPF
Continuous manufacturing: In-line virus spiking for connected chromatography applications
No full textno abstrac
International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of Nonrodent Ocular Tissues.
No full textThe INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/ inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in ocular tissues (eyes and glands and ocular adnexa) from laboratory nonrodent species (rabbits, dogs, minipigs, and nonhuman primates) used in nonclinical safety studies with an emphasis on ocular-targeted dosing. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes descriptions and visual depictions of spontaneous lesions and lesions induced by exposure to various test materials. A widely accepted and utilized internationally harmonized nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists
Importance of tailored non-clinical safety testing of novel antimalarial drugs: Industry best-practice.
No full textMalaria is an acute, debilitating parasitic illness. There were 249 million cases of malaria in 2022, resulting in 608,000 deaths globally, 76% of which were children ≤5 years. The unique nature of this disease (recurrences leading to re-treatments and numerous organ systems affected), specific clinical treatment regimens, poor compliance, and diversity of affected populations (predominantly pediatrics, women of childbearing potential, pregnant and lactating women), often makes standard testing approaches inadequate, and tailor-made safety assessments are more appropriate. We provide best practice recommendations based on company experience for the non-clinical safety assessment of antimalarial drugs, with a focus on small molecules since they represent the majority of drug candidates for this illness. We focus on specific testing considerations for repeat dose toxicity studies, including combination toxicity assessments, since new drug treatment regimens typically foresee short treatment durations to improve compliance (i.e., 1 day) with combinations of compounds to improve efficacy and limit potential resistance. Due to the target population, the timing of reproductive, developmental, and juvenile toxicity studies may be earlier than general testing roadmaps for other small molecule drugs. In conclusion, key recommendations presented should enable a more effective and efficient development path whilst protecting clinical trial participants and patients
Adventures with the β2-adrenoceptor Receptor: A Career Long Interest in Agonising One of the Most Widely Studied GPCRs.
No full textDrug discovery is a multi-disciplinary effort in which groups with expertise in a range of areas combine in a unified way to achieve a common goal: to deliver a clinical candidate to evaluate a hypothesis for improving human health. As a medicinal chemist this environment has provided multiple opportunities to be involved in cross-discipline interactions that have been both rewarding and led to outcomes that would not have been possible without an intimate interdisciplinary curiosity. Within this article I aim to share some of my experiences with the β2-adrenoceptor that have fostered such synergistic relationships with several disciplines, but in particular with in vitro pharmacologists looking at different ways to stimulate this G protein-coupled receptor (GPCR). This interest now spans over a quarter of a century and has been intertwined with the delivery of three clinical candidates
Effect of Midostaurin on the Pharmacokinetics of P-gp, BCRP, and CYP2D6 Substrates: Assessing Potential Drug-Drug Interactions in Healthy Participants
No full textPurpose: Midostaurin, approved for FLT3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is mainly metabolized by cytochrome P450 (CYP) 3A4. Midostaurin exhibited potential inhibitory effects on P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic
anion-transporting polyprotein 1B1, and CYP2D6 in in vitro studies. This study investigated the pharmacokinetic (PK) effects of midostaurin on P-gp (digoxin), BCRP (rosuvastatin) and CYP2D6 (dextromethorphan) substrates in healthy adults.
Methods: This was an open-label, single-sequence, phase I clinical study evaluating the effect of single-dose midostaurin (100 mg) on the PK of digoxin and rosuvastatin (Arm 1), and dextromethorphan (Arm 2). Participants were followed up for safety 30 days after last dose. In addition, the effect of midostaurin on the PK of dextrorphan was assessed in participants with functional CYP2D6 genes in Arm 2.
Results: The effect of midostaurin on digoxin was minor and resulted in total exposure (AUC) and peak plasma concentration (Cmax) that were only 20% higher. The effect on rosuvastatin was mild and led to an increase in AUCs of approximately 37%-48% and of 100% in Cmax. There was no increase in the primary PK parameters (AUCs and Cmax) of dextromethorphan in the presence of midostaurin. The study treatments were very well tolerated with no occurance of severe adverse events (AEs), AEs of grade ≥2, or deaths.
Conclusion: Midostaurin showed only a minor inhibitory effect on P gp, a mild inhibitory effect on BCRP, and no inhibitory effect on CYP2D6 substrates. Study treatments were well-tolerated in healthy adults
Oxidative cyclization reagents reveal tryptophan cation-π interactions.
No full textMethods for selective covalent modification of amino acids on proteins can enable a diverse array of applications, spanning probes and modulators of protein function to proteomics1-3. Owing to their high nucleophilicity, cysteine and lysine residues are the most common points of attachment for protein bioconjugation chemistry through acid-base reactivity3,4. Here we report a redox-based strategy for bioconjugation of tryptophan, the rarest amino acid, using oxaziridine reagents that mimic oxidative cyclization reactions in indole-based alkaloid biosynthetic pathways to achieve highly efficient and specific tryptophan labelling. We establish the broad use of this method, termed tryptophan chemical ligation by cyclization (Trp-CLiC), for selectively appending payloads to tryptophan residues on peptides and proteins with reaction rates that rival traditional click reactions and enabling global profiling of hyper-reactive tryptophan sites across whole proteomes. Notably, these reagents reveal a systematic map of tryptophan residues that participate in cation-π interactions, including functional sites that can regulate protein-mediated phase-separation processes
Wurster Technology-Assisted Step-by-Step Engineering of Multi-layered Pellets (Sprinkles): Microscopy, Micro-CT, and e-Tongue-Based Analysis.
No full textThe advancement in the formulation and characterization techniques have paved the path for development of new as well as modification of existing dosage forms. The present work explores the role of micro-computed tomography (micro-CT) as advanced characterization technique for multi-layered-coated pellets to ascertain the quality of coated pellets. The work further explored in-house e-tongue technique for understanding palatability of formulation in early stages of development thus by reducing clinical taste evaluation time. The developed multi-layered-coated pellets were characterized using microscopy (optical and electron microscopy). The obtained results demonstrated formation of spherical-shaped pellets with uniform coating. The uniform coating was further confirmed by results obtained from scanning electron microscopy (SEM) and cross-sectional SEM analysis, which showed visible difference in pellet surface before and after multi-layered coating. The micro-CT results confirmed the visible demarcation of layers (drug and polymer, i.e., hydroxypropyl methylcellulose (HPMC) and eudragit (EPO)) along with uniform thickness of various layering. The dissolution study of developed pellets suggested the role of layering EPO on drug release from pellets. The e-tongue analysis proved to be an excellent tool for early prediction of taste masking of drug via multi-layered pellets and can serve as potential platform for taste masking with high specificity. The overall results suggest the suitability of developed multi-layered platform as efficient dosage form (sprinkle) in pediatric/geriatric product development