Early dysregulation of GSK3β impairs mitochondrial activity in Fragile X Syndrome.

The finely tuned regulation of mitochondria activity is essential for proper brain development. Fragile X Syndrome (FXS), the leading cause of inherited intellectual disability, is a neurodevelopmental disorder in which mitochondrial dysfunction has been increasingly implicated. This study investigates the role of Glycogen Synthase Kinase 3β (GSK3β) in FXS.

Molecular Insights Into Binding and Activation of the Human KCNQ2 Channel by Retigabine.

Voltage-gated potassium channels of the Kv7.x family are involved in a plethora of biological processes across many tissues in animals, and their misfunctioning could lead to several pathologies ranging from diseases caused by neuronal hyperexcitability, such as epilepsy, or traumatic injuries and painful diabetic neuropathy to autoimmune disorders. Among the members of this family, the Kv7.

Testing Phenotypes in Response to GSK3 Inhibitors: SB216763 versus AFC03127.

Glycogen synthase kinase 3 (GSK3) is a proline-directed serine-threonine kinase that is associated with several neurological disorders, including Alzheimer's disease and fragile X syndrome (FXS). We tested the efficacy of a novel GSK3 inhibitor AFC03127, which was developed by Angelini Pharma, in comparison to the metabotropic glutamate receptor 5 inhibitor 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and the GSK3 inhibitor SB216763 in and assays in mice, a mouse model useful for the study of FXS. The assay tested susceptibility to audiogenic-induced seizures (AGS) whereas the assays assessed biomarker expression and dendritic spine length and density in cultured primary neurons as a function of drug dose.

Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening.

The major cause of bacterial resistance to β-lactams is the production of hydrolytic β-lactamase enzymes. Nowadays, the combination of β-lactam antibiotics with β-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging β-lactamases, such as OXA-48, pose the need for novel and effective treatments.

Structure-based virtual screening to identify novel carnitine acetyltransferase activators.

Carnitine acetyltransferase (CAT) is an attractive therapeutic target against fibrosis. We have identified few CAT activators through structure-based virtual screening followed by molecular dynamics simulations for assessment of the binding mode. A set of 10,000 drug-like molecules properly filtered from an initial chemical library of 13 M commercially available compounds were docked into the active site.

The mood stabilizing properties of AF3581, a novel potent GSK-3β inhibitor.

Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders.

Optimization of Indazole-Based GSK-3 Inhibitors with Mitigated hERG Issue and Activity in a Mood Disorder Model.

Bipolar disorders still represent a global unmet medical need and pose a requirement for novel effective treatments. In this respect, glycogen synthase kinase 3β (GSK-3β) aberrant activity has been linked to the pathophysiology of several disease conditions, including mood disorders. Therefore, the development of GSK-3β inhibitors with good efficacy and safety profile associated with high brain exposure is required.

Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches.

The interest of research groups and pharmaceutical companies to discover novel GSK-3β inhibitors has increased over the years considering the involvement of this enzyme in many pathophysiological processes and diseases. Along this line, we recently reported on 1H-indazole-3-carboxamide (INDZ) derivatives -, showing good GSK-3β inhibition activity. However, they suffered from generally poor central nervous system (CNS) permeability.

Antibacterial activity of novel dual bacterial DNA type II topoisomerase inhibitors.

In this study, a drug discovery programme that sought to identify novel dual bacterial topoisomerase II inhibitors (NBTIs) led to the selection of six optimized compounds. In enzymatic assays, the molecules showed equivalent dual-targeting activity against the DNA gyrase and topoisomerase IV enzymes of Staphylococcus aureus and Escherichia coli. Consistently, the compounds demonstrated potent activity in susceptibility tests against various Gram-positive and Gram-negative reference species, including ciprofloxacin-resistant strains.

Virtual Screening Approach and Investigation of Structure-Activity Relationships To Discover Novel Bacterial Topoisomerase Inhibitors Targeting Gram-Positive and Gram-Negative Pathogens.

Bacterial resistance is increasing rapidly, requiring urgent identification of new antibacterial drugs that are effective against multidrug-resistant pathogens. Novel bacterial topoisomerase inhibitors (NBTIs) provide a new strategy for investigating the well-validated DNA gyrase and topoisomerase IV targets while preventing cross-resistance issues. On this basis, starting from a virtual screening campaign and subsequent structure-based hit optimization guided by X-ray studies, a novel class of piperazine-like NBTIs with outstanding enzymatic activity against and DNA gyrase and topoisomerase IV was identified.

Molecular basis for the different interactions of congeneric substrates with the polyspecific transporter AcrB.

The drug/proton antiporter AcrB, which is part of the major efflux pump AcrABZ-TolC in Escherichia coli, is the paradigm transporter of the resistance-nodulation-cell division (RND) superfamily. Despite the impressive ability of AcrB to transport many chemically unrelated compounds, only a few of these ligands have been co-crystallized with the protein. Therefore, the molecular features that distinguish good substrates of the pump from poor ones have remained poorly understood to date.

A Novel Multi-step Virtual Screening for the Identification of Human and Mouse mPGES-1 Inhibitors.

We present here the development of a novel virtual screening protocol combining Structure-based and Ligand-based drug design approaches for the identification of mouse mPGES-1 inhibitors. We used the existing 3D structural data of the murine enzyme to hypothesize the inhibitors binding mode, which was the starting point for docking simulations, shape screening, and pharmacophore hypothesis screening. The protocol allowed the identification of 16 mouse mPGES-1 inhibitors with low micromolar activity, which, notably, also inhibit the human enzyme in the same concentration range.

Structure-Based Discovery of 1H-Indazole-3-carboxamides as a Novel Structural Class of Human GSK-3 Inhibitors.

An in silico screening procedure was performed to select new inhibitors of glycogen synthase kinase 3β (GSK-3β), a serine/threonine protein kinase that in the last two decades has emerged as a key target in drug discovery, having been implicated in multiple cellular processes and linked with the pathogenesis of several diseases. GSK-3β inhibitors might prove useful as therapeutic compounds in the treatment of conditions associated with elevated levels of enzyme activity, such as type-2 diabetes and neurological disorders, for example, Alzheimer's disease, bipolar disorder, neuronal cell death, stroke, and depression. In this work, virtual screening studies were applied to proprietary compound libraries, and the functional activities of selected compounds were assayed on human GSK-3β.

Hit Optimization of 5-Substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors with in Vivo Activity in Model of Mood Disorders.

Novel treatments for bipolar disorder with improved efficacy and broader spectrum of activity are urgently needed. Glycogen synthase kinase 3β (GSK-3β) has been suggested to be a key player in the pathophysiology of bipolar disorder. A series of novel GSK-3β inhibitors having the common N-[(1-alkylpiperidin-4-yl)methyl]-1H-indazole-3-carboxamide scaffold were prepared taking advantage of an X-ray cocrystal structure of compound 5 with GSK-3β.

Murine mPGES-1 3D structure elucidation and inhibitors binding mode predictions by homology modeling and site-directed mutagenesis.

Microsomal prostaglandin E synthase-1 (mPGES-1) constitutes an inducible glutathione-dependent integral membrane protein that catalyzes the oxido-reduction of cyclooxygenase derived PGH₂ into PGE₂. mPGES-1 is an essential enzyme involved in a variety of human diseases or pathological conditions, such as rheumatoid arthritis, fever, and pain; it is therefore regarded as a primary target for development of next-generation anti-inflammatory drugs. Several compounds targeting human mPGES-1 have been reported in the literature.

Discovery and pharmacological profile of new 1H-indazole-3-carboxamide and 2H-pyrrolo[3,4-c]quinoline derivatives as selective serotonin 4 receptor ligands.

Since the discovery of the serotonin 4 receptor (5-HT(4)R), a large number of receptor ligands have been studied. The safety concerns and the lack of market success of these ligands have mainly been attributed to their lack of selectivity. In this study we describe the discovery of N-[(4-piperidinyl)methyl]-1H-indazole-3-carboxamide and 4-[(4-piperidinyl)methoxy]-2H-pyrrolo[3,4-c]quinoline derivatives as new 5-HT(4)R ligands endowed with high selectivity over the serotonin 2A receptor and human ether-a-go-go-related gene potassium ion channel.

New anti-viral drugs for the treatment of the common cold.

Human Rhinovirus (HRV) is the most important aetiologic agent of common cold in adults and children. HRV is a single-stranded, positive sense RNA virus and, despite the high level of conservation among different serotypes, sequence alignment of viral protease 3C with mammalian protease reveals no homology. Thus, protease 3C is an optimal target for the development of anti-HRV agents.