Design, Synthesis, and In Vitro Characterization of a Tryptamine-Based Visible-Light Photoswitchable 5-HTR Ligand Showing Efficacy Preference for β-Arrestin over Mini-Gq.

The serotonin 2A receptor (5-HTR) modulates various neurotransmitter systems and is implicated in psychiatric disorders, including depression and schizophrenia. Despite progress, the detailed mechanisms of signaling at the 5-HTR and its therapeutic implications remain unclear, warranting further exploration. Overcoming the limitations of conventional pharmacology, photopharmacology addresses issues such as spatial selectivity and spatiotemporal resolution by incorporating light as an additional external control element.

Genetic Variants and Clinical Phenotyping in 39 Pediatric Patients with Neuropathic Pain.

Pathogenic variants in voltage-gated sodium channels (VGSCs) may cause disturbed sensory function, including small fiber neuropathy (SFN) in adults, but little is known about their role in children and adolescents.A total of 39 prospectively enrolled children (age 12.03 ± 4.

Structural Systems Biology Toolkit (SSBtoolkit): From Molecular Structure to Subcellular Signaling Pathways.

Here, we introduce the Structural Systems Biology (SSB) toolkit, a Python library that integrates structural macromolecular data with systems biology simulations to model signal-transduction pathways of G-protein-coupled receptors (GPCRs). Our framework streamlines simulation and analysis of the mathematical models of GPCRs cellular pathways, facilitating the exploration of the signal-transduction kinetics induced by ligand-GPCR interactions: the dose-response of the ligand can be modeled, along with the corresponding change in the concentration of other signaling molecular species over time, like for instance [Ca] or [cAMP]. SSB toolkit brings to light the possibility of easily investigating the subcellular effects of ligand binding on receptor activation, even in the presence of genetic mutations, thereby enhancing our understanding of the intricate relationship between ligand-target interactions at the molecular level and the higher-level cellular and (patho)physiological response mechanisms.

Clostebol detection after transdermal and transmucosal contact. A systematic review.

Introduction: To analyze the available evidence about the correlation between the presence of detectable amounts of clostebol metabolites in urine and the transdermal or transmucosal contact of clostebol.

Content: A systematic review was performed. A systematic search was conducted in PubMed/MEDLINE, Scopus, Web of Science and the Cochrane library databases.

Application of a novel RNA-protein interaction assay to develop inhibitors blocking RNA-binding of the HuR protein.

RNA-protein interactions play an important regulatory role in several biological processes. For example, the RNA-binding protein HuR (human antigen R) binds to its target mRNAs and regulates their translation, stability, and subcellular localization. HuR is involved in the pathogenic processes of various diseases.

Rational Design of Ligands with Optimized Residence Time.

Residence time (RT) refers to the duration that a drug remains bound to its target, affecting its efficacy and pharmacokinetic properties. RTs are key factors in drug design, yet the structure-based design of ligands with desired RTs is still in its infancy. Here, we propose that a combination of cutting-edge molecular dynamics-based methods with classical computer-aided ligand design can help identify ligands that bind not only with high affinity to their target receptors but also with the required residence time to fully exert their beneficial action without causing undesired side effects.

Refining Ligand Poses in RNA/Ligand Complexes of Pharmaceutical Relevance: A Perspective by QM/MM Simulations and NMR Measurements.

Predicting the binding poses of ligands targeting RNAs is challenging. Here, we propose that using first-principles quantum mechanics/molecular mechanics (QM/MM) simulations, which incorporate automatically polarization effects, can help refine the structural determinants of ligand/RNA complexes in aqueous solution. In fact, recent advances in massively parallel computer architectures (such as exascale machines), combined with the power of machine learning, are greatly expanding the domain of applicability of these types of notoriously expensive simulations.

KIRA6 is an Effective and Versatile Mast Cell Inhibitor of IgE-mediated Activation.

Mast cell (MC)-driven allergic diseases are constantly expanding and require the development of novel pharmacological MC stabilizers. Allergen/antigen (Ag)-triggered activation via crosslinking of the high-affinity receptor for IgE (FcεRI) is fundamentally regulated by SRC family kinases, for example, LYN and FYN, exhibiting positive and negative functions. We report that KIRA6, an inhibitor for the endoplasmic reticulum stress sensor IRE1α, suppresses IgE-mediated MC activation by inhibiting both LYN and FYN.

Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution.

Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein human α-synuclein (AS), a key player in Parkinson's disease and other synucleinopathies. Here, molecular simulations provide insight into the structural ensemble of phosphorylated AS. The simulations allow us to suggest that phosphorylation significantly impacts the structural content of the physiological AS conformational ensemble in aqueous solution, as the phosphate group is mostly solvated.

A conserved peptide-binding pocket in HyNaC/ASIC ion channels.

The only known peptide-gated ion channels-FaNaCs/WaNaCs and HyNaCs-belong to different clades of the DEG/ENaC family. FaNaCs are activated by the short neuropeptide FMRFamide, and HyNaCs by Hydra RFamides, which are not evolutionarily related to FMRFamide. The FMRFamide-binding site in FaNaCs was recently identified in a cleft atop the large extracellular domain.

Depletion of membrane cholesterol modifies structure, dynamic and activation of Na1.7.

Cholesterol is a major component of plasma membranes and plays a significant role in actively regulating the functioning of several membrane proteins in humans. In this study, we focus on the role of cholesterol depletion on the voltage-gated sodium channel Na1.7, which is primarily expressed in the peripheral sensory neurons and linked to various chronic inherited pain syndromes.

Traumatic Brain Injury in Patients under Anticoagulant Therapy: Review of Management in Emergency Department.

The best management of patients who suffer from traumatic brain injury (TBI) while on oral anticoagulants is one of the most disputed problems of emergency services. Indeed, guidelines, clinical decision rules, and observational studies addressing this topic are scarce and conflicting. Moreover, relevant issues such as the specific treatment (and even definition) of mild TBI, rate of delayed intracranial injury, indications for neurosurgery, and anticoagulant modulation are largely empiric.

How exascale computing can shape drug design: A perspective from multiscale QM/MM molecular dynamics simulations and machine learning-aided enhanced sampling algorithms.

Molecular simulations are an essential asset in the first steps of drug design campaigns. However, the requirement of high-throughput limits applications mainly to qualitative approaches with low computational cost, but also low accuracy. Unlocking the potential of more rigorous quantum mechanical/molecular mechanics (QM/MM) models combined with molecular dynamics-based free energy techniques could have a tremendous impact.

Mutational rescue of the activity of high-fidelity Cas9 enzymes.

Programmable DNA endonucleases derived from bacterial genetic defense systems, exemplified by CRISPR-Cas9, have made it significantly easier to perform genomic modifications in living cells. However, unprogrammed, off-target modifications can have serious consequences, as they often disrupt the function or regulation of non-targeted genes and compromise the safety of therapeutic gene editing applications. High-fidelity mutants of Cas9 have been established to enable more accurate gene editing, but these are typically less efficient.

Unexpected Single-Ligand Occupancy and Negative Cooperativity in the SARS-CoV-2 Main Protease.

Many homodimeric enzymes tune their functions by exploiting either negative or positive cooperativity between subunits. In the SARS-CoV-2 Main protease (Mpro) homodimer, the latter has been suggested by symmetry in most of the 500 reported protease/ligand complex structures solved by macromolecular crystallography (MX). Here we apply the latter to both covalent and noncovalent ligands in complex with Mpro.

Physical Chemistry of Chloroquine Permeation through the Cell Membrane with Atomistic Detail.

We provide a molecular-level description of the thermodynamics and mechanistic aspects of drug permeation through the cell membrane. As a case study, we considered the antimalaria FDA approved drug chloroquine. Molecular dynamics simulations of the molecule (in its neutral and protonated form) were performed in the presence of different lipid bilayers, with the aim of uncovering key aspects of the permeation process, a fundamental step for the drug's action.

EphrinA5 regulates cell motility by modulating Snhg15/DNA triplex-dependent targeting of DNMT1 to the Ncam1 promoter.

Cell-cell communication is mediated by membrane receptors and their ligands, such as the Eph/ephrin system, orchestrating cell migration during development and in diverse cancer types. Epigenetic mechanisms are key for integrating external "signals", e.g.

Three-dimensional evaluation of symmetry in facial palsy reanimation using stereophotogrammetric devices: A series of 15 cases.

Facial palsy can severely compromise quality of life, significantly altering the harmony and symmetry of the face, which can be restored by surgical rehabilitation. The aim of the study was the quantification of facial symmetry following facial reanimation. Fifteen consecutive adult patients were surgically treated through triple innervation for reanimation of flaccid unilateral facial paralysis (contralateral facial nerve, masseteric nerve, and hypoglossal nerve) and fascia lata graft for definition of the nasolabial sulcus.

A community effort in SARS-CoV-2 drug discovery.

The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against COVID-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors.

Low Molecular Weight Inhibitors Targeting the RNA-Binding Protein HuR.

The RNA-binding protein human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. This protein has been progressively recognized as a relevant therapeutic target for several pathologies, like cancer, neurodegeneration, as well as inflammation. Inhibitors of mRNA binding to HuR might thus be beneficial against a variety of diseases.

AI-based identification of therapeutic agents targeting GPCRs: introducing ligand type classifiers and systems biology.

Identifying ligands targeting G protein coupled receptors (GPCRs) with novel chemotypes other than the physiological ligands is a challenge for screening campaigns. Here we present an approach that identifies novel chemotype ligands by combining structural data with a random forest agonist/antagonist classifier and a signal-transduction kinetic model. As a test case, we apply this approach to identify novel antagonists of the human adenosine transmembrane receptor type 2A, an attractive target against Parkinson's disease and cancer.

Metadynamics simulations of ligands binding to protein surfaces: a novel tool for rational drug design.

Structure-based drug design protocols may encounter difficulties to investigate poses when the biomolecular targets do not exhibit typical binding pockets. In this study, by providing two concrete examples from our labs, we suggest that the combination of metadynamics free energy methods (validated against affinity measurements), along with experimental structural information (by X-ray crystallography and NMR), can help to identify the poses of ligands on protein surfaces. The simulation workflow proposed here was implemented in a widely used code, namely GROMACS, and it could straightforwardly be applied to various drug-design campaigns targeting ligands' binding to protein surfaces.

SPEADI: Accelerated Analysis of IDP-Ion Interactions from MD-Trajectories.

The disordered nature of Intrinsically Disordered Proteins (IDPs) makes their structural ensembles particularly susceptible to changes in chemical environmental conditions, often leading to an alteration of their normal functions. A Radial Distribution Function (RDF) is considered a standard method for characterizing the chemical environment surrounding particles during atomistic simulations, commonly averaged over an entire or part of a trajectory. Given their high structural variability, such averaged information might not be reliable for IDPs.

Predictions of the Poses and Affinity of a Ligand over the Entire Surface of a NEET Protein: The Case of Human MitoNEET.

Human NEET proteins contain two [2Fe-2S] iron-sulfur clusters, bound to three Cys residues and one His residue. They exist in two redox states. Recently, these proteins have revealed themselves as attractive drug targets for mitochondrial dysfunction-related diseases, such as type 2 diabetes, Wolfram syndrome 2, and cancers.