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Readable research linked to original sources
Browse normalized, publication-ready research with direct links to its evidence and source.
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Readable research linked to original sources
Browse normalized, publication-ready research with direct links to its evidence and source.
37 articles
Newest firstSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells when the spike receptor-binding domain (RBD) engages angiotensin-converting enzyme 2 (ACE2). Cannabinoid scaffolds have recently been reported to bind S1/RBD, block spike-mediated membrane fusion, and modulate host inflammatory pathways, making them attractive candidates for entry inhibition. Here, we applied an integrated computational…
Open article record in new tab ↗GPR55 is an orphan G protein-coupled receptor (GPCR) and represents a promising drug target for cancer, inflammation, and metabolic diseases. The endogenous activation of lipid GPCRs can be solely mediated by membrane components and different lipids have been proposed as endogenous activators of GPR55, such as cannabinoids and lysophosphatidylinositols. Here, we determine high-resolution cryo-electron microscopy s…
TRPV3 represents both temperature- and ligand-activated transient receptor potential (TRP) channel. Physiologically relevant opening of TRPV3 channels by heat has been captured structurally, while opening by agonists has only been observed in structures of mutant channels. Here, we present cryo-EM structures that illuminate opening and inactivation of wild-type human TRPV3 in response to binding of two types of ag…
The cannabinoid receptor 1 (CB1R) regulates synaptic transmission in the central nervous system, but also has important roles in the peripheral organs controlling cellular metabolism. While earlier generations of brain penetrant CB1R antagonists advanced to the clinic for their effective treatment of obesity, such molecules were ultimately shown to exhibit negative effects on central reward pathways that thwarted…
The design of dualsteric/bitopic agents as single chemical entities able to simultaneously interact with both the orthosteric and an allosteric binding site represents a novel approach in medicinal chemistry. Biased dualsteric/bitopic agents could enhance certain signaling pathways while diminishing the others that cause unwanted side effects. We have designed, synthesized, and functionally characterized the first…
The detection and staging of Alzheimer's disease (AD) using non-invasive imaging biomarkers is of substantial clinical importance. Positron emission tomography (PET) provides readouts to uncover molecular alterations in the brains of AD patients with high sensitivity and specificity. A variety of amyloid-β (Aβ) and tau PET tracers are already available for the clinical diagnosis of AD, but there is still a lack of…
Open article record in new tab ↗Molecular dynamic (MD) simulations have become a common tool to study the pathway of ligand entry to the orthosteric binding site of G protein-coupled receptors. Here, we have combined MD simulations and site-directed mutagenesis to study the binding process of the potent JWH-133 agonist to the cannabinoid CB2 receptor (CB2R). In CB2R, the N-terminus and extracellular loop 2 fold over the ligand binding pocket, bl…
Transient receptor potential vanilloid 2 (TRPV2) is involved in many critical physiological and pathophysiological processes, making it a promising drug target. Here we present cryo-electron microscopy (cryo-EM) structures of rat TRPV2 in lipid nanodiscs activated by 2-aminoethoxydiphenyl borate (2-APB) and propose a TRPV2-specific 2-ABP binding site at the interface of S5 of one monomer and the S4-S5 linker of th…
The cannabinoid receptors (CB1/CB2) and the T-type calcium channels are involved in disorders associated with both physiological pain and depressive behaviors. Valuable pharmacological species carbazole derivatives such as the NMP-4, NMP-7, and NMP-181 (Neuro Molecular Production) regulate both biological entities. In this work, DFT calculations were performed to characterize theoretically their structural and che…
Although the 3D structures of active and inactive cannabinoid receptors type 2 (CB2) are available, neither the X-ray crystal nor the cryo-EM structure of CB2-orthosteric ligand-modulator has been resolved, prohibiting the drug discovery and development of CB2 allosteric modulators (AMs). In the present work, we mainly focused on investigating the potential allosteric binding site(s) of CB2. We applied different a…
Cannabinoid receptor ligands are renowned as being therapeutically crucial for treating diverse health disorders. Phenylspirodrimanes are meroterpenoids with unique and varied structural scaffolds, which are mainly reported from the Stachybotrys genus and display an array of bioactivities. In this work, 114 phenylspirodrimanes reported from Stachybotrys chartarum were screened for their CB2 agonistic potential usi…
The endocannabinoid system plays an essential role in the regulation of analgesia and human immunity, and Cannabinoid Receptor 2 (CB2) has been proved to be an ideal target for the treatment of liver diseases and some cancers. In this study, we identified CB2 antagonists using a three-step "deep learning-pharmacophore-molecular docking" virtual screening approach. From the ChemDiv database (1,178,506 compounds), 1…
The Sterling Research Group identified pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory pain reliever. As drug design progressed, the ability of AAI analogs to block prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the CB1 cannabinoid receptor, a G-protein-coupled receptor (GPCR) abundant in the brain. Several laboratories applied computati…
Open article record in new tab ↗The activation of cannabinoid CB1 receptors (CB1R) by Δ9-tetrahydrocannabinol (THC), the main component of Cannabis sativa, induces analgesia. CB1R activation, however, also causes cognitive impairment via the serotonin 5HT2A receptor (5HT2AR), a component of a CB1R-5HT2AR heteromer, posing a serious drawback for cannabinoid therapeutic use. We have shown that peptides reproducing CB1R transmembrane (TM) helices 5…
Open article record in new tab ↗The activation of the human cannabinoid receptor type II (CB2R) is known to mediate analgesic and anti-inflammatory processes without the central adverse effects related to cannabinoid receptor type I (CB1R). In this work we describe the synthesis and evaluation of a novel series of N-aryl-2-pyridone-3-carboxamide derivatives tested as human cannabinoid receptor type II (CB2R) agonists. Different cycloalkanes link…
Cellobiohydrolases directly convert crystalline cellulose into cellobiose and are of biotechnological interest to achieve efficient biomass utilization. As a result, much research in the field has focused on identifying cellobiohydrolases that are very fast. Cellobiohydrolase A from the bacterium Cellulomonas fimi (CfCel6B) and cellobiohydrolase II from the fungus Trichoderma reesei (TrCel6A) have similar catalyti…
To discover novel inhibitors that target the influenza polymerase basic protein 2 (PB2) cap-binding domain (CBD), commercial ChemBridge compound libraries containing 384,796 compounds were screened using a cascade docking of LibDock-LigandFit-GOLD, and 60 compounds were selected for testing with cytopathic effect (CPE) inhibition assays and surface plasmon resonance (SPR) assay. Ten compounds were identified to re…
Open article record in new tab ↗Crotoxin, from the venom of the South American rattlesnake Crotalus durissus terrificus, is a potent heterodimeric presynaptic β-neurotoxin that exists in individual snake venom as a mixture of isoforms of a basic phospholipase A2 (PLA2) subunit (CBa2, CBb, CBc, and CBd) and acidic subunit (CA1-4). Specific natural mutations in CB isoforms are implicated in functional differences between crotoxin isoforms. The thr…
Depression has a multifactorial etiology that arises from environmental, psychological, genetic, and biological factors. Environmental stress and genetic factors acting through immunological and endocrine responses generate structural and functional changes in the brain, inducing neurogenesis and neurotransmission dysfunction. Terpineol, monoterpenoid alcohol, has shown immunomodulatory and neuroprotective effects…
Monoacylglycerol lipase (MAGL) is an important enzyme of the endocannabinoid system that catalyzes the degradation of the major endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL is associated with pathological conditions such as pain, inflammation and neurodegenerative diseases like Parkinson's and Alzheimer's disease. Furthermore, elevated levels of MAGL have been found in aggressive breast, ovarian and melanom…