Prediction of human pharmacokinetics from chemical structure: combining mechanistic modeling with machine learning.

Pharmacokinetics (PK) is the result of a complex interplay between compound properties and physiology, and a detailed characterization of a molecule's PK during preclinical research is key to understanding the relationship between applied dose, exposure, and pharmacological effect. Predictions of human PK based on the chemical structure of a compound are highly desirable to avoid advancing compounds with unfavorable properties early on and to reduce animal testing, but data to train such models are scarce. To address this problem, we combine well-established physiologically based pharmacokinetic models with Deep Learning models for molecular property prediction into a hybrid model to predict PK parameters for small molecules directly from chemical structure.

BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models.

The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition.

A deep neural network: mechanistic hybrid model to predict pharmacokinetics in rat.

An important aspect in the development of small molecules as drugs or agrochemicals is their systemic availability after intravenous and oral administration. The prediction of the systemic availability from the chemical structure of a potential candidate is highly desirable, as it allows to focus the drug or agrochemical development on compounds with a favorable kinetic profile. However, such predictions are challenging as the availability is the result of the complex interplay between molecular properties, biology and physiology and training data is rare.

Identification of the Highly Active, Species Cross-Reactive Complex I Inhibitor BAY-179.

Mitochondria are key regulators of energy supply and cell death. Generation of ATP within mitochondria occurs through oxidative phosphorylation (OXPHOS), a process which utilizes the four complexes (complex I-IV) of the electron transport chain and ATP synthase. Certain oncogenic mutations (, LKB1 or mIDH) can further enhance the reliance of cancer cells on OXPHOS for their energetic requirements, rendering cells sensitive to complex I inhibition and highlighting the potential value of complex I as a therapeutic target.

Preparation of Cell Extracts by Cryogrinding in an Automated Freezer Mill.

The ease of genetic manipulation and the strong evolutionary conservation of eukaryotic cellular machinery in the budding yeast Saccharomyces cerevisiae has made it a pre-eminent genetic model organism. However, since efficient protein isolation depends upon optimal disruption of cells, the use of yeast for biochemical analysis of cellular proteins is hampered by its cell wall which is expensive to digest enzymatically (using lyticase or zymolyase), and difficult to disrupt mechanically (using a traditional bead beater, a French press or a coffee grinder) without causing heating of samples, which in turn causes protein denaturation and degradation. Although manual grinding of yeast cells under liquid nitrogen (LN2) using a mortar and pestle avoids overheating of samples, it is labor intensive and subject to variability in cell lysis between operators.

Gut Commensal-Induced IκBζ Expression in Dendritic Cells Influences the Th17 Response.

Intestinal commensal bacteria can have a large impact on the state of health and disease of the host. Regulation of Th17 cell development by gut commensals is known to contribute to their dichotomous role in promoting gut homeostasis and host defense, or development of autoimmune diseases. Yet, the underlying mechanisms remain to be fully elucidated.

The Otteroo: A Case Series Exploring Its Potential to Support Physical Therapy Intervention in Infants with or at Risk for Developmental Delay.

The objective of this case series was to examine the potential of the Otteroo as a tool to support physical therapy intervention in infants with or at risk for developmental disability. The Otteroo is a float with potential for use in aquatic therapy sessions or as part of a home exercise program. By tracking the amount of use and caregiver perception of the child's response, we aimed to generate an understanding of the Otteroo's potential as a family-based adjunct to physical therapy.

Prediction of Oral Bioavailability in Rats: Transferring Insights from in Vitro Correlations to (Deep) Machine Learning Models Using in Silico Model Outputs and Chemical Structure Parameters.

Oral administration of drug products is a strict requirement in many medical indications. Therefore, bioavailability prediction models are of high importance for prioritization of compound candidates in the drug discovery process. However, oral exposure and bioavailability are difficult to predict, as they are the result of various highly complex factors and/or processes influenced by the physicochemical properties of a compound, such as solubility, lipophilicity, or charge state, as well as by interactions with the organism, for instance, metabolism or membrane permeation.

Flagellin hypervariable region determines symbiotic properties of commensal Escherichia coli strains.

Escherichia coli represents a classical intestinal gram-negative commensal. Despite this commensalism, different E. coli strains can mediate disparate immunogenic properties in a given host.

Binding Kinetics Survey of the Drugged Kinome.

Target residence time is emerging as an important optimization parameter in drug discovery, yet target and off-target engagement dynamics have not been clearly linked to the clinical performance of drugs. Here we developed high-throughput binding kinetics assays to characterize the interactions of 270 protein kinase inhibitors with 40 clinically relevant targets. Analysis of the results revealed that on-rates are better correlated with affinity than off-rates and that the fraction of slowly dissociating drug-target complexes increases from early/preclinical to late stage and FDA-approved compounds, suggesting distinct contributions by each parameter to clinical success.

Symbiotic gut commensal bacteria act as host cathepsin S activity regulators.

Cathepsin S (CTSS) is a lysosomal protease whose activity regulation is important for MHC-II signaling and subsequent activation of CD4 T cell mediated immune responses. Dysregulation of its enzymatic activity or enhanced secretion into extracellular environments is associated with the induction or progression of several autoimmune diseases. Here we demonstrate that commensal intestinal bacteria influence secretion rates and intracellular activity of host CTSS and that symbiotic bacteria, i.

Novel Immunomodulatory Flagellin-Like Protein FlaC in Campylobacter jejuni and Other Campylobacterales.

The human diarrheal pathogens Campylobacter jejuni and Campylobacter coli interfere with host innate immune signaling by different means, and their flagellins, FlaA and FlaB, have a low intrinsic property to activate the innate immune receptor Toll-like receptor 5 (TLR5). We have investigated here the hypothesis that the unusual secreted, flagellin-like molecule FlaC present in C. jejuni, C.

Localisation and protein-protein interactions of the Helicobacter pylori taxis sensor TlpD and their connection to metabolic functions.

The Helicobacter pylori energy sensor TlpD determines tactic behaviour under low energy conditions and is important in vivo. We explored protein-protein interactions of TlpD and their impact on TlpD localisation and function. Pull-down of tagged TlpD identified protein interaction partners of TlpD, which included the chemotaxis histidine kinase CheAY2, the central metabolic enzyme aconitase (AcnB) and the detoxifying enzyme catalase (KatA).

Inhibition of Histone Deacetylases Permits Lipopolysaccharide-Mediated Secretion of Bioactive IL-1β via a Caspase-1-Independent Mechanism.

Histone deacetylase (HDAC) inhibitors (HDACi) are clinically approved anticancer drugs that have important immune-modulatory properties. We report the surprising finding that HDACi promote LPS-induced IL-1β processing and secretion in human and murine dendritic cells and murine macrophages. HDACi/LPS-induced IL-1β maturation and secretion kinetics differed completely from those observed upon inflammasome activation.

TLR signaling-induced CD103-expressing cells protect against intestinal inflammation.

Background: Toll-like receptor (TLR) expression in patients with inflammatory bowel disease is increased when compared with healthy controls. However, the impact of TLR signaling during inflammatory bowel disease is not fully understood.

Methods: In this study, we used a murine model of acute phase inflammation in bone marrow chimeric mice to investigate in which cell type TLR2/4 signal induction is important in preventing intestinal inflammation and how intestinal dendritic cells are influenced.

Estimating HIV-1 fitness characteristics from cross-sectional genotype data.

Despite the success of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV)-1 infection, virological failure due to drug resistance development remains a major challenge. Resistant mutants display reduced drug susceptibilities, but in the absence of drug, they generally have a lower fitness than the wild type, owing to a mutation-incurred cost. The interaction between these fitness costs and drug resistance dictates the appearance of mutants and influences viral suppression and therapeutic success.

Quantifying the degree of persistence in random amoeboid motion based on the Hurst exponent of fractional Brownian motion.

Amoebae explore their environment in a random way, unless external cues like, e.g., nutrients, bias their motion.

NOD2 stimulation by Staphylococcus aureus-derived peptidoglycan is boosted by Toll-like receptor 2 costimulation with lipoproteins in dendritic cells.

Mutations in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) play an important role in the pathogenesis of Crohn's disease. NOD2 is an intracellular pattern recognition receptor (PRR) that senses bacterial peptidoglycan (PGN) structures, e.g.

Endotoxicity of lipopolysaccharide as a determinant of T-cell-mediated colitis induction in mice.

Background & Aims: The intestinal microbiota is an important determinant of the mucosal response. In patients with inflammatory bowel diseases, the mucosal immune system has inappropriate interactions with the intestinal microbiota. We investigated how the composition of the intestinal microbiota affects its endotoxicity and development of colitis in mice.

Strength training for a child with suspected developmental coordination disorder.

Background: Children with developmental coordination disorder (DCD) demonstrate difficulty with feedforward motor control and use varied compensatory strategies.

Purpose: To examine gross motor function changes following strength training in a child with motor control difficulties.

Case Description: A girl aged 6 years 11 months, with apraxia and hypotonia, and demonstrating motor delays consistent with DCD.

HIV quasispecies dynamics during pro-active treatment switching: impact on multi-drug resistance and resistance archiving in latent reservoirs.

The human immunodeficiency virus (HIV) can be suppressed by highly active anti-retroviral therapy (HAART) in the majority of infected patients. Nevertheless, treatment interruptions inevitably result in viral rebounds from persistent, latently infected cells, necessitating lifelong treatment. Virological failure due to resistance development is a frequent event and the major threat to treatment success.