Drug Discovery Approaches to Target E3 Ligases.

Targeting E3 ligases is a challenging area in drug discovery. Despite the human genome encoding for more than 600 E3 ubiquitin ligases, only a handful of E3 ligases have been pharmacologically modulated or exploited for targeted protein degradation (TPD) strategies. The main obstacle for hijacking these E3 ligases is the lack of small-molecule ligands.

Proximity-Induced Pharmacology for Amyloid-Related Diseases.

Proximity-induced pharmacology (PIP) for amyloid-related diseases is a cutting-edge approach to treating conditions such as Alzheimer's disease and other forms of dementia. By bringing small molecules close to amyloid-related proteins, these molecules can induce a plethora of effects that can break down pathogenic proteins and reduce the buildup of plaques. One of the most promising aspects of this drug discovery modality is that it can be used to target specific types of amyloid proteins, such as the beta-amyloid protein that is commonly associated with Alzheimer's disease.

Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress.

Soluble epoxide hydrolase (sEH) is a drug target with the potential for therapeutic utility in the areas of inflammation, neurodegenerative disease, chronic pain, and diabetes, among others. Proteolysis-targeting chimeras (PROTACs) molecules offer new opportunities for targeting sEH, due to its capacity to induce its degradation. Here, we describe that the new ALT-PG2, a PROTAC that degrades sEH protein in the human hepatic Huh-7 cell line, in isolated mouse primary hepatocytes, and in the liver of mice.

Unveiling the Multitarget Anti-Alzheimer Drug Discovery Landscape: A Bibliometric Analysis.

Multitarget anti-Alzheimer agents are the focus of very intensive research. Through a comprehensive bibliometric analysis of the publications in the period 1990-2020, we have identified trends and potential gaps that might guide future directions. We found that: (i) the number of publications boomed by 2011 and continued ascending in 2020; (ii) the linked-pharmacophore strategy was preferred over design approaches based on fusing or merging pharmacophores or privileged structures; (iii) a significant number of in vivo studies, mainly using the scopolamine-induced amnesia mouse model, have been performed, especially since 2017; (iv) China, Italy and Spain are the countries with the largest total number of publications on this topic, whereas Portugal, Spain and Italy are the countries in whose scientific communities this topic has generated greatest interest; (v) acetylcholinesterase, β-amyloid aggregation, oxidative stress, butyrylcholinesterase, and biometal chelation and the binary combinations thereof have been the most commonly pursued, while combinations based on other key targets, such as tau aggregation, glycogen synthase kinase-3β, NMDA receptors, and more than 70 other targets have been only marginally considered.

Discovery of Novel BRD4 Ligand Scaffolds by Automated Navigation of the Fragment Chemical Space.

Fragment-based drug discovery (FBDD) is a very effective hit identification method. However, the evolution of fragment hits into suitable leads remains challenging and largely artisanal. Fragment evolution is often scaffold-centric, meaning that its outcome depends crucially on the chemical structure of the starting fragment.

Analysis and prediction of produced water quantity and quality in the Permian Basin using machine learning techniques.

Appropriate produced water (PW) management is critical for oil and gas industry. Understanding PW quantity and quality trends for one well or all similar wells in one region would significantly assist operators, regulators, and water treatment/disposal companies in optimizing PW management. In this research, historical PW quantity and quality data in the New Mexico portion (NM) of the Permian Basin from 1995 to 2019 was collected, pre-processed, and analyzed to understand the distribution, trend and characteristics of PW production for potential beneficial use.

Synthesis, Characterization and HPLC Analysis of the (1,2,5)-Diastereomer and the Enantiomer of the Clinical Candidate AR-15512.

AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1,2,5), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis.

Probiotic lactobacilli as a promising strategy to ameliorate disorders associated with intestinal inflammation induced by a non-steroidal anti-inflammatory drug.

Damage to the small intestine caused by non-steroidal anti-inflammatory drugs (NSAIDs) occurs more frequently than in the upper gastrointestinal tract, is more difficult to diagnose and no effective treatments exist. Hence, we investigated whether probiotics can control the onset of this severe condition in a murine model of intestinal inflammation induced by the NSAID, indomethacin. Probiotic supplementation to mice reduce the body weight loss, anemia, shortening of the small intestine, cell infiltration into the intestinal tissue and the loss of Paneth and Goblet cells associated with intestinal inflammation.

Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer's Disease.

The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with 3 compounds in clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's disease (AD).

Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson's Disease: A New Therapeutic Strategy.

Neuroinflammation is a crucial process associated with the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Several pieces of evidence suggest an active role of lipid mediators, especially epoxy-fatty acids (EpFAs), in the genesis and control of neuroinflammation; 14,15-epoxyeicosatrienoic acid (14,15-EET) is one of the most commonly studied EpFAs, with anti-inflammatory properties. Soluble epoxide hydrolase (sEH) is implicated in the hydrolysis of 14,15-EET to its corresponding diol, which lacks anti-inflammatory properties.

Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M.

Background: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued.

Modulating Ligand Dissociation through Methyl Isomerism in Accessory Sites: Binding of Retinol to Cellular Carriers.

Due to the poor aqueous solubility of retinoids, evolution has tuned their binding to cellular proteins to address specialized physiological roles by modulating uptake, storage, and delivery to specific targets. With the aim to disentangle the structure-function relationships in these proteins and disclose clues for engineering selective carriers, the binding mechanism of the two most abundant retinol-binding isoforms was explored by using enhanced sampling molecular dynamics simulations and surface plasmon resonance. The distinctive dynamics of the entry portal site in the species was crucial to modulate retinol dissociation.

Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis.

Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y.

Probiotic bacteria cell walls stimulate the activity of the intestinal epithelial cells and macrophage functionality.

The effect of oral administration of probiotic bacteria cell walls (PBCWs) in the stimulation of the immune system in healthy BALB/c mice was evaluated. We focused our investigation mainly on intestinal epithelial cells (IECs) which are essential for coordinating an adequate mucosal immune response and on the functionality of macrophages. The probiotic bacteria and their cell walls were able to stimulate the IECs exhibiting an important activation and cytokine releases.

Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition.

Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels.

Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology.

Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug discovery. Recent years have seen an explosion of interest in developing small molecules binding to bromodomains, the readers of acetyl-lysine modifications. A plethora of co-crystal structures has motivated focused fragment-based design and optimization programs within both industry and academia.

Multigram synthesis and in vivo efficacy studies of a novel multitarget anti-Alzheimer's compound.

We describe the multigram synthesis and in vivo efficacy studies of a donepezil‒huprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimer's disease (AD). Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic CL4176 and CL2006 Caenorhabditis elegans strains expressing human Aβ42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by Aβ42.

Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal-antiplasmodial activity.

Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process.

Evaluation of immune response, microbiota, and blood markers after probiotic bacteria administration in obese mice induced by a high-fat diet.

Objective: Obesity is associated with alterations in intestinal microbiota and immunity. The aim of this study was to determine the effect of probiotic Lactobacillus casei CRL 431 administration on intestinal and humoral immune response, clinical parameters, and gut microbiota was evaluated using a high-fat diet to induce obesity in a mouse model.

Methods: Adult mice received a conventional balanced diet or a high-fat diet supplemented with milk, milk fermented by Lactobacillus casei (FM), L.

Shogaol-huprine hybrids: dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties.

Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaol-huprine hybrids, purported to hit several key targets involved in Alzheimer's disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS.

Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein-Protein Interactions?

Modulation of protein-protein interactions (PPIs) with small molecules has been hampered by a lack of lucid methods capable of reliably identifying high-quality hits. In fragment screening, the low ligand efficiencies associated with PPI target sites pose significant challenges to fragment binding detection. Here, we investigate the requirements for ligand-based NMR techniques to detect rule-of-three compliant fragments that form part of known high-affinity inhibitors of the PPI between the von Hippel-Lindau protein and the alpha subunit of hypoxia-inducible factor 1 (pVHL:HIF-1α).

Exploring the structural basis of the selective inhibition of monoamine oxidase A by dicarbonitrile aminoheterocycles: role of Asn181 and Ile335 validated by spectroscopic and computational studies.

Since cyanide potentiates the inhibitory activity of several monoamine oxidase (MAO) inhibitors, a series of carbonitrile-containing aminoheterocycles was examined to explore the role of nitriles in determining the inhibitory activity against MAO. Dicarbonitrile aminofurans were found to be potent, selective inhibitors against MAO A. The origin of the MAO A selectivity was identified by combining spectroscopic and computational methods.