Ongoing phase 2 agents for multiple sclerosis: could we break the phase 3 trial deadlock?

Introduction: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system. While disease-modifying therapies have significantly improved the management of relapsing MS, progressive MS remains a major clinical challenge.

Areas Covered: This review provides a general overview of recent and ongoing phase 2 clinical trials investigating treatments for MS, summarizing emerging results when available.

Altered desensitization and internalization patterns of rodent versus human glucose-dependent insulinotropic polypeptide (GIP) receptors. An important drug discovery challenge.

Background And Purpose: The gut hormone glucose-dependent insulinotropic polypeptide (GIP) signals via the GIP receptor (GIPR), resulting in postprandial potentiation of glucose-stimulated insulin secretion. The translation of results from rodent studies to human studies has been challenged by the unexpected effects of GIPR-targeting compounds. We, therefore, investigated the variation between species, focusing on GIPR desensitization and the role of the receptor C-terminus.

Molecular insights into atypical modes of β-arrestin interaction with seven transmembrane receptors.

β-arrestins (βarrs) are multifunctional proteins involved in signaling and regulation of seven transmembrane receptors (7TMRs), and their interaction is driven primarily by agonist-induced receptor activation and phosphorylation. Here, we present seven cryo-electron microscopy structures of βarrs either in the basal state, activated by the muscarinic receptor subtype 2 (M2R) through its third intracellular loop, or activated by the βarr-biased decoy D6 receptor (D6R). Combined with biochemical, cellular, and biophysical experiments, these structural snapshots allow the visualization of atypical engagement of βarrs with 7TMRs and also reveal a structural transition in the carboxyl terminus of βarr2 from a β strand to an α helix upon activation by D6R.

On the construction of LIECE models for the serotonin receptor 5-HT[Formula: see text]R.

Computer-aided approaches to ligand design need to balance accuracy with speed. This is particularly true for one of the key parameters to be optimized during ligand development, the free energy of binding ([Formula: see text]G[Formula: see text]). Here, we developed simple models based on the Linear Interaction Energy approximation to free energy calculation for a G protein-coupled receptor, the serotonin receptor 2A, and critically evaluated their accuracy.

Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare.

Precision Medicine implies a deep understanding of inter-individual differences in health and disease that are due to genetic and environmental factors. To acquire such understanding there is a need for the implementation of different types of technologies based on artificial intelligence (AI) that enable the identification of biomedically relevant patterns, facilitating progress towards individually tailored preventative and therapeutic interventions. Despite the significant scientific advances achieved so far, most of the currently used biomedical AI technologies do not account for bias detection.