A membrane permeability database for nonpeptidic macrocycles.

The process of developing new drugs is arduous and costly, particularly for targets classified as "difficult-to-drug." Macrocycles show a particular ability to modulate difficult-to-drug targets, including protein-protein interactions, while still allowing oral administration. However, the determination of membrane permeability, critical for reaching intracellular targets and for oral bioavailability, is laborious and expensive.

Impact of Linker Composition on VHL PROTAC Cell Permeability.

The discovery of cell permeable and orally bioavailable von Hippel-Lindau (VHL) proteolysis targeting chimeras (PROTACs) is challenging as their structures locates them at, or beyond, the outer limits of oral druggable space. We have designed a set of nine VHL PROTACs and found that the linker had a profound impact on passive cell permeability. Determination of the solution ensembles in a nonpolar solvent revealed that high permeability was correlated to the ability of the PROTACs to adopt folded conformations that have a low solvent accessible 3D polar surface area.

ESR Essentials: basic physics of MR safety-practice recommendations by the European Society for Magnetic Resonance in Medicine and Biology.

Objectives: The use of magnetic resonance imaging (MRI) is safe from a long-term perspective since there are no known cumulative risks for patients or personnel. However, the technique comes with several acute risks associated with the powerful electromagnetic fields that are necessary to produce medical images. These risks include, among other things, a projectile hazard, loud noise, and the risk of heating.

Autoantibodies to joint-related peptides as predictive markers in early rheumatoid arthritis.

Objective: For better management of rheumatoid arthritis (RA), new biomarkers are needed to predict the development of different disease courses. This study aims to identify autoantibodies against epitopes on proteins in the joints and to predict disease outcome in patients with new onset RA.

Methods: Sera from new onset RA patients from the Swedish BARFOT and TIRA-2 cohorts (n = 1986) were screened for autoantibodies to selected peptides (JointIDs) in a bead-based multiplex flow immunoassay.

Altered probe pressure and body position increase diagnostic accuracy for men and women in detecting hepatic steatosis using quantitative ultrasound.

Objectives: To evaluate the diagnostic performance of ultrasound guided attenuation parameter (UGAP) for evaluating liver fat content with different probe forces and body positions, in relation to sex, and compared with proton density fat fraction (PDFF).

Methods: We prospectively enrolled a metabolic dysfunction-associated steatotic liver disease (MASLD) cohort that underwent UGAP and PDFF in the autumn of 2022. Mean UGAP values were obtained in supine and 30° left decubitus body position with normal 4 N and increased 30 N probe force.

Exploring the chemical space of orally bioavailable PROTACs.

A principal challenge in the discovery of proteolysis targeting chimeras (PROTACs) as oral medications is their bioavailability. To facilitate drug design, it is therefore essential to identify the chemical space where orally bioavailable PROTACs are more likely to be situated. To this aim, we extracted structure-bioavailability insights from published data using traditional 2D descriptors, thereby shedding light on their potential and limitations as drug design tools.

Low-dose acetylsalicylic acid reduces local inflammation and tissue perfusion in dense breast tissue in postmenopausal women.

Purpose: One major risk factor for breast cancer is high mammographic density. It has been estimated that dense breast tissue contributes to ~ 30% of all breast cancer. Prevention targeting dense breast tissue has the potential to improve breast cancer mortality and morbidity.

Molecular chameleons in drug discovery.

Molecular chameleons possess a flexibility that allows them to dynamically shield or expose polar functionalities in response to the properties of the environment. Although the concept of molecular chameleons was introduced already in 1970, interest in them has grown considerably since the 2010s, when drug discovery has focused to an increased extent on new chemical modalities. Such modalities include cyclic peptides, macrocycles and proteolysis-targeting chimeras, all of which reside in a chemical space far from that of traditional small-molecule drugs.

Retrospective comparison between MRI examinations during radiographer-administered intranasal sedation or general anesthesia.

Introduction: In order for young children to be able to undergo a Magnetic Resonance Imaging (MRI) examination, general anesthesia is often required. The aim of this study was to compare the image quality, times, and costs of the examinations of infant brains performed with MRI either during sedation with dexmedetomidine administered by radiographers or anesthesia with propofol administered by anesthesia staff.

Methods: This study was a quantitative retrospective study of 27 consecutive standard brain examinations performed under sedation or anesthesia, involving 15 children under sedation and 12 under anesthesia.

Radiographers' confidence in handling iodine based contrast media hypersensitivity reactions.

Introduction: Adverse reactions to iodinated contrast media, which is used during computed tomography (CT) examinations, are rare. As a result, radiographers have limited experience handling those situations and may feel uncertainty and a lack of confidence. The aim of this study was to investigate radiographers' confidence in handling hypersensitivity reactions to contrast media during CT examinations.

Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice.

B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells.

Therapy targeting antigen-specific T cells by a peptide-based tolerizing vaccine against autoimmune arthritis.

A longstanding goal has been to find an antigen-specific preventive therapy, i.e., a vaccine, for autoimmune diseases.

Structure-based virtual screening discovers potent and selective adenosine A receptor antagonists.

Development of subtype-selective leads is essential in drug discovery campaigns targeting G protein-coupled receptors (GPCRs). Herein, a structure-based virtual screening approach to rationally design subtype-selective ligands was applied to the A and A adenosine receptors (AR and AR). Crystal structures of these closely related subtypes revealed a non-conserved subpocket in the binding sites that could be exploited to identify AR selective ligands.

Macrocycles in Drug Discovery─Learning from the Past for the Future.

We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs are mainly used in infectious disease and oncology, while oncology is the major indication for the clinical candidates and in the literature Most macrocyclic drugs bind to targets that have difficult to drug binding sites. Natural products have provided 80-90% of the drugs and clinical candidates, whereas macrocycles in ChEMBL have less complex structures.

Design of Drug Efficacy Guided by Free Energy Simulations of the β -Adrenoceptor.

G-protein-coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high-resolution receptor structures are available. We performed molecular dynamics simulations of the β adrenergic receptor in active and inactive conformations to assess if binding free energy calculations can predict differences in ligand efficacy for closely related compounds.

Corrigendum: A head-to-head comparison of myocardial strain by fast-strain encoding and feature tracking imaging in acute myocardial infarction.

[This corrects the article DOI: 10.3389/fcvm.2022.

Predictive Modeling of PROTAC Cell Permeability with Machine Learning.

Approaches for predicting proteolysis targeting chimera (PROTAC) cell permeability are of major interest to reduce resource-demanding synthesis and testing of low-permeable PROTACs. We report a comprehensive investigation of the scope and limitations of machine learning-based binary classification models developed using 17 simple descriptors for large and structurally diverse sets of cereblon (CRBN) and von Hippel-Lindau (VHL) PROTACs. For the VHL PROTAC set, kappa nearest neighbor and random forest models performed best and predicted the permeability of a blinded test set with >80% accuracy ( ≥ 0.

Autoantibodies to Disease-Related Proteins in Joints as Novel Biomarkers for the Diagnosis of Rheumatoid Arthritis.

Objective: This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints.

Methods: We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity.

Conformational Sampling Deciphers the Chameleonic Properties of a VHL-Based Degrader.

Chameleonicity (the capacity of a molecule to adapt its conformations to the environment) may help to identify orally bioavailable drugs in the beyond-Rule-of-5 chemical space. Computational methods to predict the chameleonic behaviour of degraders have not yet been reported and the identification of molecular chameleons still relies on experimental evidence. Therefore, there is a need to tune predictions with experimental data.

Simulation Reveals the Chameleonic Behavior of Macrocycles.

Conformational analysis is central to the design of bioactive molecules. It is particularly challenging for macrocycles due to noncovalent transannular interactions, steric interactions, and ring strain that are often coupled. Herein, we simulated the conformations of five macrocycles designed to express a progression of increasing complexity in environment-dependent intramolecular interactions and verified the results against NMR measurements in chloroform and dimethyl sulfoxide.