Investigation of the Anti-Inflammatory Properties of Bioactive Compounds from : In Silico Evaluation of Cyclooxygenase Enzyme Inhibition and Pharmacokinetic Profiling.

In a landmark study, oleocanthal (OLC), a major phenolic in extra virgin olive oil (EVOO), was found to possess anti-inflammatory activity similar to ibuprofen, involving inhibition of cyclooxygenase (COX) enzymes. EVOO is a rich source of bioactive compounds including fatty acids and phenolics; however, the biological activities of only a small subset of compounds associated with have been explored. Here, the OliveNet library (consisting of over 600 compounds) was utilized to investigate olive-derived compounds as potential modulators of the arachidonic acid pathway.

Identification and Evaluation of Olive Phenolics in the Context of Amine Oxidase Enzyme Inhibition and Depression: In Silico Modelling and In Vitro Validation.

The Mediterranean diet well known for its beneficial health effects, including mood enhancement, is characterised by the relatively high consumption of extra virgin olive oil (EVOO), which is rich in bioactive phenolic compounds. Over 200 phenolic compounds have been associated with , and of these, only a relatively small fraction have been characterised. Utilising the OliveNet library, phenolic compounds were investigated as potential inhibitors of the epigenetic modifier lysine-specific demethylase 1 (LSD1).

Utilization of the EpiMed Coronabank Chemical Collection to identify potential SARS-CoV-2 antivirals: in silico studies targeting the nsp14 ExoN domain and PL naphthalene binding site.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 29 proteins including four structural, 16 nonstructural (nsps), and nine accessory proteins (https://epimedlab.org/sars-cov-2-proteome/). Many of these proteins contain potential targetable sites for the development of antivirals.

Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells.

Key Points: Set7 knockout improves diabetic glomerular structure and function and prevents diabetes-induced endothelial–mesenchymal transition (EDMT) by regulating Igfbp5. Set7 knockdown prevents, and (R)-PFI-2 hydrochloride reverses, diabetes-induced EDMT by regulating insulin growth factor binding protein 5. Set7 regulates the phenotypic EDMT switch, and inhibiting the methyltransferase attenuates glomerular injury in diabetic kidney disease.

Identification of Potential Modulators of a Pathogenic G Protein-Gated Inwardly Rectifying K Channel 4 Mutant: Investigation in the Context of Drug Discovery for Hypertension.

Genetic abnormalities have been associated with primary aldosteronism, a major cause of secondary hypertension. This includes mutations in the gene, which encodes G protein-gated inwardly rectifying K channel 4 (GIRK4). For example, the substitution of glycine with glutamic acid gives rise to the pathogenic GIRK4 mutation, which alters channel selectivity, making it more permeable to Na and Ca.

A repository of COVID-19 related molecular dynamics simulations and utilisation in the context of nsp10-nsp16 antivirals.

The coronavirus disease 2019 (COVID-19) pandemic highlighted the importance of establishing systems and infrastructure to develop vaccines, antiviral drugs, and therapeutic antibodies against emerging pathogens. Typical drug discovery processes involve targeting suitable proteins to effect pathogen replication or to attenuate host responses, by examining either large chemical databases or protein-protein interactions. Following initial screens, molecular dynamics (MD) simulations are critical for gaining further insight into molecular interactions.

γH2AX in mouse embryonic stem cells: Distribution during differentiation and following γ-irradiation.

Phosphorylated histone H2AX (γH2AX) represents a sensitive molecular marker of DNA double-strand breaks (DSBs) and is implicated in stem cell biology. We established a model of mouse embryonic stem cell (mESC) differentiation and examined the dynamics of γH2AX foci during the process. Our results revealed high numbers of γH2AX foci in undifferentiated mESCs, decreasing as the cells differentiated towards the endothelial cell lineage.

Chronicling the 3-year evolution of the COVID-19 pandemic: analysis of disease management, characteristics of major variants, and impacts on pathogenicity.

Announced on December 31, 2019, the novel coronavirus arising in Wuhan City, Hubei Province resulted in millions of cases and lives lost. Following intense tracking, coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization (WHO) in 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the cause of COVID-19 and the continuous evolution of the virus has given rise to several variants.

EpiMed Coronabank Chemical Collection: Compound selection, ADMET analysis, and utilisation in the context of potential SARS-CoV-2 antivirals.

Antiviral drugs are important for the coronavirus disease 2019 (COVID-19) response, as vaccines and antibodies may have reduced efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Antiviral drugs that have been made available for use, albeit with questionable efficacy, include remdesivir (Veklury®), nirmatrelvir-ritonavir (Paxlovid™), and molnupiravir (Lagevrio®). To expand the options available for COVID-19 and prepare for future pandemics, there is a need to investigate new uses for existing drugs and design novel compounds.

Characterization of K562 cells: uncovering novel chromosomes, assessing transferrin receptor expression, and probing pharmacological therapies.

Human erythroleukemic K562 cells represent the prototypical cell culture model of chronic myeloid leukemia (CML). The cells are pseudo-triploid and positive for the Philadelphia chromosome. Therefore, K562 cells have been widely used for investigating the BCR/ABL1 oncogene and the tyrosine kinase inhibitor, imatinib-mesylate.

Identification of dietary compounds that interact with the circadian clock machinery: Molecular docking and structural similarity analysis.

The molecular clock is vital for regulating circadian rhythms in various physiological processes, and its dysregulation is associated with multiple diseases. As such, the use of small molecule modulators to regulate the molecular clock presents a promising therapeutic approach. In this study, we generated a homology model of the human circadian locomotor output cycles kaput (CLOCK) protein to evaluate its ligand binding sites.

Sulforaphane prevents and reverses allergic airways disease in mice via anti-inflammatory, antioxidant, and epigenetic mechanisms.

Sulforaphane has been investigated in human pathologies and preclinical models of airway diseases. To provide further mechanistic insights, we explored L-sulforaphane (LSF) in the ovalbumin (OVA)-induced chronic allergic airways murine model, with key hallmarks of asthma. Histological analysis indicated that LSF prevented or reversed OVA-induced epithelial thickening, collagen deposition, goblet cell metaplasia, and inflammation.

Molecular dynamics simulations highlight the altered binding landscape at the spike-ACE2 interface between the Delta and Omicron variants compared to the SARS-CoV-2 original strain.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.

The SARS-CoV-2 helicase as a target for antiviral therapy: Identification of potential small molecule inhibitors by in silico modelling.

Although vaccines that provide protection against severe illness from coronavirus disease (COVID-19) have been made available, emerging variant strains of severe acute respiratory syndrome 2 coronavirus 2 (SARS-CoV-2) are of concern. A different research direction involves investigation of antiviral therapeutics. In addition to structural proteins, the SARS-CoV-2 non-structural proteins are of interest and this includes the helicase (nsp13).

Identification of novel bioactive compounds from Olea europaea by evaluation of chemical compounds in the OliveNet™ library: in silico bioactivity and molecular modelling, and in vitro validation of hERG activity.

Background: As highlighted in the OliveNet™ library, Olea europaea consists of a diverse collection of chemical compounds. We have classified over 600 compounds into 13 main classes and 47 subclasses. Various compounds, including oleuropein and hydroxytyrosol, have been investigated for their potential beneficial effects in multiple human pathologies.

Alpha-lipoic acid analogues in the regulation of redox balance in epilepsy: A molecular docking and simulation study.

Objective: Oxidative stress is one of the pathophysiological mechanisms implicated in drug-resistant epilepsy. Recurrent seizures and prolonged treatment with anti-seizure medicines (ASMs) can produce reactive oxygen species (ROS) resulting in neuronal cell damage, cell toxicity, and cell death. This damage may contribute to the loss of efficacy of anti-seizure medicines.

Investigation of small molecule inhibitors of the SARS-CoV-2 papain-like protease by all-atom microsecond modelling, PELE Monte Carlo simulations, and activity inhibition.

The SARS-CoV-2 papain-like (PL) protease is essential for viral replication. We investigated potential antiviral effects of hypericin relative to the well-known noncovalent PL inhibitor GRL-0617. Molecular dynamics and PELE Monte Carlo simulations highlight favourable binding of hypericin and GRL-0617 to the naphthalene binding pocket of PL.

investigation of DNA minor groove binding bibenzimidazoles in the context of UV phototherapy.

The versatility of DNA minor groove binding bibenzimidazoles extends to applications in cancer therapy, beyond their typical use as DNA stains. In the context of UV phototherapy, a series of halogenated analogues designated -, -, and -iodoHoechst have been investigated. Phototoxicity involves dehalogenation of the ligands following exposure to UV light, resulting in the formation of a carbon-centred radical.

Small molecule interactions with the SARS-CoV-2 main protease: In silico all-atom microsecond MD simulations, PELE Monte Carlo simulations, and determination of in vitro activity inhibition.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing COVID-19 pandemic. With some notable exceptions, safe and effective vaccines, which are now being widely distributed globally, have largely begun to stabilise the situation. However, emerging variants of concern and vaccine hesitancy are apparent obstacles to eradication.

investigation to identify potential small molecule inhibitors of the RNA-dependent RNA polymerase (RdRp) nidovirus RdRp-associated nucleotidyltransferase domain.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) is a promising target for antiviral drugs. In this study, a chemical library (n = 300) was screened against the nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain. Blind docking was performed using a selection of 30 compounds and nine ligands were chosen based on their docking scores, safety profile, and availability.

Inhibition of interferon-stimulated gene 15 and lysine 48-linked ubiquitin binding to the SARS-CoV-2 papain-like protease by small molecules: studies.

The SARS-CoV-2 papain-like protease (PL) is a suitable target for drug development, and its deubiquitinating and deISGylating activities have also been reported. In this study, molecular docking was used to investigate the binding properties of a selection of dietary compounds and naphthalene-based inhibitors to the previously characterised binding site of GRL-0617. The structures of the SARS-CoV-2 and SARS-CoV PL in complex with interferon-stimulated gene 15 (ISG15) and lysine 48 (K48)-linked diubiquitin were utilised.

Interaction of small molecules with the SARS-CoV-2 papain-like protease: In silico studies and in vitro validation of protease activity inhibition using an enzymatic inhibition assay.

The SARS-CoV-2 virus is causing COVID-19, an ongoing pandemic, with extraordinary global health, social, and political implications. Currently, extensive research and development efforts are aimed at producing a safe and effective vaccine. In the interim, small molecules are being widely investigated for antiviral effects.

Identification of Small Molecule Inhibitors of the Deubiquitinating Activity of the SARS-CoV-2 Papain-Like Protease: Molecular Docking Studies and Enzymatic Activity Assay.

COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 virus with important political, socio-economic, and public health consequences. Inhibiting replication represents an important antiviral approach, and in this context two viral proteases, the SARS-CoV-2 main and papain-like proteases (PL), which cleave pp1a and pp1ab polypeptides, are critical. Along with protease activity, the PL possesses deubiquitinating activity, which is important in immune regulation.