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LF is a bioactive protein, derived from colostrum and milk that has been found to possess various immunomodulatory, iron chelating, and antimicrobial properties, especially in its apo-form. Recent studies have demonstrated the functionality of LF in attaching to the S proteins of SARS-CoV-2, thereby preventing it from interacting with the ACE-2 receptor. However, the molecular mechanism mediating the process is poorly understood. In this study, molecular docking and MD simulations coupled with free energy calculations were applied to elucidate the key interaction of apo-LF and its N-lobe and C-lobe derivative forms with the RBD of coronavirus S proteins. This has also been extended into evaluating the L452R mutant, which is associated with the delta variant of SARS-CoV-2. The results demonstrate the efficacy of the apo-LF C-lobe in binding to the RBD of both variants, primarily through electrostatic attractions between the acidic residues of the former and the basic residues of each RBD. Furthermore, due to the additional arginine in the L452R variant, the interaction between the C-lobe and the latter is stronger, resulting in a more favourable binding and tightly bound structure. The simulations highlight that the C-lobe, followed by full-length apo-LF can form a multimeric complex with the RBD of SARS-CoV-2, indicating their potential use as novel therapeutics, particularly the cleaved C-lobe of apo-LF to disrupt the S proteins from binding to the host ACE-2 receptor. Communicated by Ramaswamy H. Sarma.

Lactoferrin is a protein, primarily found in milk that has attracted the interest of the food industries due to its health properties. Nevertheless, the instability of lactoferrin has limited its commercial application. Recent studies have focused on encapsulation to enhance the stability of lactoferrin. However, the molecular insights underlying the changes of structural properties of lactoferrin and the interaction with protectants remain poorly understood. Computational approaches have proven useful in understanding the structural properties of molecules and the key binding with other constituents. In this review, comprehensive information on the structure and function of lactoferrin and the binding with various molecules for food purposes are reviewed, with a special emphasis on the use of molecular dynamics simulations. The results demonstrate the application of modeling and simulations to determine key residues of lactoferrin responsible for its stability and interactions with other biomolecular components under various conditions, which are also associated with its functional benefits. These have also been extended into the potential creation of enhanced lactoferrin for commercial purposes. This review provides valuable strategies in designing novel nutraceuticals for food science practitioners and those who have interests in acquiring familiarity with the application of computational modeling for food and health purposes.

Supplementary Methods from Receptor-Mediated DNA-Targeted Photoimmunotherapy

Supplementary Figures 1-2, Tables 1-2 from Receptor-Mediated DNA-Targeted Photoimmunotherapy

DNA-minor groove binding bibenzimidazole ligands, such as ortho-iodoHoechst bind in the minor groove of DNA in AT-rich regions. Upon photodehalogenation of the DNA ligand a carbon-centred radical is formed.

Graphical abstract, The SARS-CoV-2 papain-like (PLpro) protease is essential for viral replication. We investigated potential antiviral effects of hypericin relative to the well-known noncovalent PLpro inhibitor GRL-0617. Molecular dynamics and PELE Monte Carlo simulations highlight favourable binding of hypericin and GRL-0617 to the naphthalene binding pocket of PLpro. Although not potent as GRL-0617 (45.8 vs 1.6µM for protease activity, respectively), in vitro fluorogenic enzymatic assays with hypericin show concentration-dependent inhibition of both PLpro protease and deubiquitinating activities. Given its use in supplementations and the FDA conditional approval of a synthetic version, further evaluation of hypericin as a potential SARS-CoV-2 antiviral is warranted.

Major depressive disorder (MDD) is considered a serious public health issue that adversely impacts an individual's quality of life and contributes significantly to the global burden of disease. The clinical heterogeneity that exists among patients limits the ability of MDD to be accurately diagnosed and currently, a symptom-based approach is utilized in many cases. Due to the complex nature of this disorder, and lack of precise knowledge regarding the pathophysiology, effective management is challenging. The aetiology and pathophysiology of MDD remain largely unknown given the complex genetic and environmental interactions that are involved. Nonetheless, the aetiology and pathophysiology of MDD have been the subject of extensive research, and there is a vast body of literature that exists. Here we overview the key hypotheses that have been proposed for the neurobiology of MDD and highlight the need for a unified model, as many of these pathways are integrated. Key pathways discussed include neurotransmission, neuroinflammation, clock gene machinery pathways, oxidative stress, role of neurotrophins, stress response pathways, the endocannabinoid and endovanilloid systems, and the endogenous opioid system. We also describe the current management of MDD, and emerging novel therapies, with particular focus on patients with treatment-resistant depression (TRD).

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. Add-on therapy with antioxidants, neuroimmunophilins, and polyphenols may thus be beneficial in drug-resistant epilepsy. In vitro and in vivo studies have shown a significant improvement in drug efficacy and seizure suppression using co-treatment of anti-seizure medication with naturally available antioxidants including alpha-lipoic acid (α-lipoic acid) from walnut; however, the underlying mechanisms of action remain to be fully understood.We undertook molecular docking and molecular dynamics simulations to determine whether alpha-lipoic acid and related analogues interacted with the human manganese superoxide dismutase (MnSOD) protein, a member of the oxidative metabolic pathway. The 3D structure of the compounds and the protein were retrieved from protein and chemical databases, binding sites were identified and ligand-protein interactions were performed.Alpha-lipoic acid and various analogues docked within a human MnSOD binding region. Docking results were validated by molecular dynamic simulation. The CMX-2043 analogue showed strong binding with MnSOD compared to alpha-lipoic acid and other analogues.Our findings provide new insights into additional mechanisms of action, which may in part, account for the antioxidant properties associated with alpha-lipoic acid and related analogues. The results support further in vitro and in vivo evaluation of these compounds to better understand their potential as add-on therapy for ASM treatment in epilepsy.

L-sulforaphane (LSF) is a naturally derived isothiocyanate derived from cruciferous vegetables that has long been known for its health benefiting effects. These include its anti-carcinogenic, antioxidant and anti-inflammatory effects. LSF also possesses antimicrobial properties, although the evidence for this is limited. Respiratory pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, S. pyogenes and respiratory syncytial virus (RSV) are leading causes of illness and death among children under five-years-old globally, especially in resource-poor countries where access to vaccines are limited or in the case of S. pyogenes and RSV, have not been licensed for use in humans. Therefore, alternate strategies to prevent and/or treat these common infectious diseases are urgently needed. This study investigated the antimicrobial effects of LSF against common respiratory pathogens, S. pneumoniae (serotypes 1 and 6B), H. influenzae type B (HiB) and non-typeable H. influenzae (NTHi), S. pyogenes and RSV in relevant human cell-based models. LSF significantly inhibited the growth of H. influenzae, but not S. pneumoniae or S. pyogenes. LSF did not improve opsonophagocytic capacity or killing by human phagocytic cell lines (HL-60s and THP-1 macrophages) for S. pneumoniae yet showed some improved killing for H. influenzae species in THP-1 macrophages. However, LSF significantly reduced RSV infection in human lung epithelial cells, associated with increased expression of cyclin D1 (CCND1) gene as well as the antioxidant genes nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HMOX-1). Overall, LSF represents an exciting avenue for further antimicrobial research, particularly as a novel therapy against H. influenzae species and RSV.

Graphical abstract, The SARS-CoV-2 papain-like protease (PLpro) 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 PLpro in complex with interferon-stimulated gene 15 (ISG15) and lysine 48 (K48)-linked diubiquitin were utilised. To predict whether compounds could potentially interfere with the binding of these cellular modifiers, docking was conducted in the absence and presence of ISG15 and K48-linked diubiquitin.

Circadian rhythms are responsible for regulating a number of physiological processes. The central oscillator is located within the suprachiasmatic nucleus (SCN) of the hypothalamus and the SCN synchronises the circadian clocks that are found in our peripheral organs through neural and humoral signalling. At the molecular level, biological clocks consist of transcription-translation feedback loops (TTFLs) and these pathways are influenced by transcription factors, post-translational modifications, signalling pathways and epigenetic modifiers. When disruptions occur in the circadian machinery, the activities of the proteins implicated in this network and the expression of core clock or clock-controlled genes (CCGs) can be altered. Circadian misalignment can also arise when there is desychronisation between our internal clocks and environmental stimuli. There is evidence in the literature demonstrating that disturbances in the circadian rhythm contribute to the pathophysiology of several diseases and disorders. This includes the metabolic syndrome and recently, it has been suggested that the 'circadian syndrome' may be a more appropriate term to use to not only describe the cardio-metabolic risk factors but also the associated comorbidities. Here we overview the molecular architecture of circadian clocks in mammals and provide insight into the effects of shift work, exposure to artificial light, food intake and stress on the circadian rhythm. The relationship between circadian rhythms, metabolic disorders and depression is reviewed and this is a topic that requires further investigation. We also describe how particular proteins involved in the TTFLs can be potentially modulated by small molecules, including pharmacological interventions and dietary compounds.

Graphical abstract, Highlights • The SARS-CoV-2 main protease (Mpro) has an important role in the viral life cycle. • Inhibition of the active site or dimerization site of Mpro can mitigate activity. • Mapping reveals a reactive pocket in the dimerization pocket at the apex of Mpro. • Blind docking shows that ligands may preferentially bind at the apex of Mpro. • Stable ligand interactions are formed at the active and apex sites of Mpro., The SARS-CoV-2 virus is causing COVID-19 resulting in an ongoing pandemic with serious health, social, and economic implications. Much research is focused in repurposing or identifying new small molecules which may interact with viral or host-cell molecular targets. An important SARS-CoV-2 target is the main protease (Mpro), and the peptidomimetic α-ketoamides represent prototypical experimental inhibitors. The protease is characterised by the dimerization of two monomers each which contains the catalytic dyad defined by Cys145 and His41 residues (active site). Dimerization yields the functional homodimer. Here, our aim was to investigate small molecules, including lopinavir and ritonavir, α-ketoamide 13b, and ebselen, for their ability to interact with the Mpro. The sirtuin 1 agonist SRT1720 was also used in our analyses. Blind docking to each monomer individually indicated preferential binding of the ligands in the active site. Site-mapping of the dimeric protease indicated a highly reactive pocket in the dimerization region at the domain III apex. Blind docking consistently indicated a strong preference of ligand binding in domain III, away from the active site. Molecular dynamics simulations indicated that ligands docked both to the active site and in the dimerization region at the apex, formed relatively stable interactions. Overall, our findings do not obviate the superior potency with respect to inhibition of protease activity of covalently-linked inhibitors such as α-ketoamide 13b in the Mpro active site. Nevertheless, along with those from others, our findings highlight the importance of further characterisation of the Mpro active site and any potential allosteric sites.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain, and function by targeting cyclooxygenase (COX) enzymes to inhibit the production of prostaglandins that facilitate inflammation. Since oleocanthal derived from Olea europaea is known to inhibit COX, we sought to characterise novel olive compounds with COX inhibitory activity using in silico techniques. Following on from part 1 of this study which identified 1-oleyltyrosol (1OL) and ligstroside derivative 2 (LG2) with COX inhibitory potential, the mechanisms of COX interactions by these selected compounds were further examined using molecular dynamics (MD) simulations. Classical MD simulations were carried out on COX-1 and COX-2 complexed with 1OL and LG2 to determine the stability and protein backbone fluctuation. Protein dynamics were examined using essential dynamics methods and network analysis, which identified that the N-terminal epidermal growth factor-like domain and membrane bound domains of COX-1 and -2 exhibited altered motions when ligands were bound. Distinct dynamical modules were identified, and that COX-2 inter-residue communications were more sensitive to ligand binding compared to COX-1. The use of various network metrics presents a novel approach in the characterisation of network behaviour of different ligands. It is proposed that inter-residue network metrics provide additional measures of the potential bioactivity of ligands, which may form a useful adjunct to conventional direct predictions of binding affinity, in determining the efficacy of potential small-molecule inhibitors. Overall, this two-part study characterises anti-inflammatory effects of low dosage dietary COX inhibitors, and provides a possible avenue for the development of therapeutics in inflammatory diseases.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to reduce pain. These target cyclooxygenase (COX) enzymes which produce inflammatory mediators. Adverse effects associated with the use of traditional NSAIDs have led to a rise in the development of alternative therapies. Derived from Olea Europaea, olive oil is a main component of the Mediterranean diet, containing phenolic compounds that contribute to its antioxidant and anti-inflammatory properties. It has previously been found that oleocanthal, a phenolic compound derived from the olive, had similar effects to ibuprofen, a commonly used NSAID. There is an abundance of olive phenolic compounds that have yet to be investigated for their anti-inflammatory properties. In this study, it was sought to identify potential olive-derived compounds with the ability to inhibit COX enzymes, and study the mechanisms using in silico approaches. Molecular docking was employed to determine the COX inhibitory potential of an olive phenolic compound library. From docking, it was determined that 1-oleyltyrosol (1OL) and ligstroside derivative 2 (LG2) demonstrated the greatest binding affinity to both COX-1 and COX-2. Interactions with these compounds were further examined using molecular dynamics simulations. The residue contributions to binding free energy were computed using Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) methods, revealing that residues Leu93, Val116, Leu352, and Ala527 in COX-1 and COX-2 were key determinants of potential inhibition. Along with part 2 of this study, this work aims to identify and characterise novel phenolic compounds which may possess COX inhibitory properties.

Graphical abstract, Highlights • The SARS-CoV-2 main protease (Mpro) is an important target against COVID-19. • Peptidomimetic α-ketoamides represent prototypical inhibitors of the SARS-CoV-2 Mpro. • We confirmed the high affinity of the α-ketoamide 13b inhibitor to SARS-CoV-2 Mpro • MD simulations highlight α-ketoamide 13b stability in Mpro compared to amoxicillin • The α-ketoamide compound class could be pursued as potential antivirals against COVID-19, The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes an illness known as COVID-19, which has been declared a global pandemic with over 2 million confirmed cases and 137,000 deaths in 185 countries and regions at the time of writing (16 April 2020), over a quarter of these cases being in the United States. In the absence of a vaccine, or an approved effective therapeutic, there is an intense interest in repositioning available drugs or designing small molecule antivirals. In this context, in silico modelling has proven to be an invaluable tool. An important target is the SARS-CoV-2 main protease (Mpro), involved in processing translated viral proteins. Peptidomimetic α-ketoamides represent prototypical inhibitors of Mpro. A recent attempt at designing a compound with enhanced pharmacokinetic properties has resulted in the synthesis and evaluation of the α-ketoamide 13b analogue. Here, we performed molecular docking and molecular dynamics simulations to further characterize the interaction of α-ketoamide 13b with the active site of the SARS-CoV-2 Mpro. We included the widely used antibiotic, amoxicillin, for comparison. Our findings indicate that α-ketoamide 13b binds more tightly (predicted GlideScore = -8.7 and -9.2 kcal/mol for protomers A and B, respectively), to the protease active site compared to amoxicillin (-5.0 and -4.8 kcal/mol). Further, molecular dynamics simulations highlight the stability of the interaction of the α-ketoamide 13b ligand with the SARS-CoV-2 Mpro (ΔG = -25.2 and -22.3 kcal/mol for protomers A and B). In contrast, amoxicillin interacts unfavourably with the protease (ΔG = +32.8 kcal/mol for protomer A), with unbinding events observed in several independent simulations. Overall, our findings are consistent with those previously observed, and highlight the need to further explore the α-ketoamides as potential antivirals for this ongoing COVID-19 pandemic.

Streptococcus pneumoniae infection can lead to pneumococcal disease, a major cause of mortality in children under the age of five years. In low- and middle-income country settings where pneumococcal disease burden is high, vaccine use is low and widespread antibiotic use has led to increased rates of multi-drug resistant pneumococci. l -sulforaphane (LSF), derived from broccoli and other cruciferous vegetables, has established anti-inflammatory, antioxidant, and anti-microbial properties. Hence, we sought to investigate the potential role of LSF against pneumococcal infection. Using a combination of in vitro and computational methods, the results showed that LSF and relevant metabolites had a potential to reduce pneumococcal adherence through modulation of host receptors, regulation of inflammation, or through direct modification of bacterial factors. Treatment with LSF and metabolites reduced pneumococcal adherence to respiratory epithelial cells. Synchrotron-Fourier transform infrared microspectroscopy (S-FTIR) revealed biochemical changes in protein and lipid profiles of lung epithelial cells following treatment with LSF or metabolites. Molecular docking studies of 116 pneumococcal and 89 host factors revealed a potent effect for the metabolite LSF-glutathione (GSH). A comprehensive list of factors involved in interactions between S. pneumoniae and host cells was compiled to construct a bacterium and host interaction network. Network analysis revealed plasminogen, fibronectin, and RrgA as key factors involved in pneumococcal-host interactions. Therefore, we propose that these constitute critical targets for direct inhibition by LSF and/or metabolites, which may disrupt pneumococcal-host adherence. Overall, our findings further enhance understanding of the potential role of LSF to modulate pneumococcal-host dynamics.

The ovalbumin-induced (OVA) chronic allergic airways murine model is a well-established model for investigating pre-clinical therapies for chronic allergic airways diseases, such as asthma. Here, we examined the effects of several experimental compounds with potential anti-asthmatic effects including resveratrol (RV), relaxin (RLN), l-sulforaphane (LSF), valproic acid (VPA), and trichostatin A (TSA) using both a prevention and reversal model of chronic allergic airways disease. We undertook a novel analytical approach using focal plane array (FPA) and synchrotron Fourier-transform infrared (S-FTIR) microspectroscopic techniques to provide new insights into the mechanisms of action of these experimental compounds. Apart from the typical biological effects, S-FTIR microspectroscopy was able to detect changes in nucleic acids and protein acetylation. Further, we validated the reduction in collagen deposition induced by each experimental compound evaluated. Although this has previously been observed with conventional histological methods, the S-FTIR technique has the advantage of allowing identification of the type of collagen present. More generally, our findings highlight the potential utility of S-FTIR and FPA-FTIR imaging techniques in enabling a better mechanistic understanding of novel asthma therapeutics.

Lactoferrin (LF) is a multi-functional protein that is primarily found in milk. The apo form of LF (apo-LF) is devoid of iron, and as a result, may serve as an iron scavenger with attendant anti-pathogenic properties, thereby, endowing apo-LF with promising health benefits. Despite these advantages, the structural stability of apo-LF may be perturbed by various processing conditions. One of the strategies employed to stabilise the activity of apo-LF is to encapsulate it as part of an oligomeric complex, composed of apo-LF, α-lactalbumin (α-La) and β-lactoglobulin (β-Lg). Accordingly, the aim of this study is to investigate the structural changes of apo-LF and its interactions with α-La and β-Lg under the temperature conditions of freeze-drying (−30, 0, and 20 °C). Using in silico approaches, molecular dynamics simulations showed apo-LF had limited structural perturbation when processed at these temperatures. Both α-La and β-Lg stabilise apo-LF by enhancing and maintaining the structural integrity and cohesion of the tertiary structure of apo-LF. These stabilities are the result of electrostatic interactions, binding apo-LF and the protective proteins into a multimeric complex. The secondary structure and the anti-bacterial derivatives in apo-LF were also sustained under these simulated conditions. Furthermore, inter-residue contact maps in apo-LF predict an increase in intramolecular contacts at simulated freeze-drying conditions, resulting in agglomeration and, therefore potential proteins dispersibility during subsequent rehydration. Overall, this work demonstrates the advantages of computational approaches to understand the macromolecular conformations, interactions, and functional implications of a multimeric complex composed of apo-LF, α-La, and β-Lg at low temperatures.

Increasingly, lactic acid bacteria have been encapsulated into food formulations because of their health advantages, including modulation of the gut microflora. However, the molecular mechanism on how these bacteria interact with the encapsulating agent, which is typically composed of milk proteins is not fully comprehended. Accordingly, molecular dynamics simulations were employed to investigate the interaction between the cell wall component of these bacteria, specifically the peptidoglycan layer and a protein complex, comprising apo-lactoferrin, β-lactoglobulin, and α-lactalbumin at spray drying temperatures (68 and 110 °C). The results demonstrate that the peptidoglycan model interacts with the posterior N-lobe of apo-lactoferrin and the three-turn α-helix of β-lactoglobulin via van der Waals, electrostatic, and non-polar solvation interactions. Free energy calculations also show higher binding affinity at 110 °C than 68 °C, indicating that elevated temperatures are essential to facilitate hydrophobic interactions between the peptidoglycan component and the N-lobe of apo-lactoferrin. Furthermore, the secondary structure and the antibacterial regions in apo-lactoferrin are maintained following thermal simulations. The simulations not only highlight the formation of a stable complex, involving the peptidoglycan component, apo-lactoferrin, β-lactoglobulin, and α-lactalbumin, but also the preservation of the functionalities of apo-lactoferrin, which may provide valuable insights into the development of novel nutraceuticals.

Graphical abstract, 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. Using cluster analysis on a 10 microsecond molecular dynamics simulation trajectory (from D.E. Shaw Research), the compounds were docked to the different conformations. On the basis of our modelling studies, oleuropein was identified as a potential lead compound.

This study employs computational techniques to investigate whether the inclusion of β-lactoglobulin and α-lactalbumin can enhance the molecular stability of apo-lactoferrin in conditions of gastric pH. Atomistic molecular dynamics simulations reveal that acidic pH results in weakened interactions between lactoferrin and the other proteins compared to those under neutral pH. Nevertheless, protein-protein dissociation free energy calculations using the umbrella sampling calculations confirm that some contacts are maintained between apo-lactoferrin and the other whey proteins, specifically the β-lactoglobulin units. This is manifested as a broad energy minimum at the intermediate inter-molecular distance of the inter-protein free energy profiles; thereby, demonstrating the formation of a nano-scale flocculant, followed by a potential gel, composed of protein particles. Practically, this property could be exploited to entrap further bioactive components within the protein matrix for novel engineered food materials. Furthermore, it was found that the anti-bacterial peptide regions of apo-lactoferrin are unaffected by the acidic pH, indicating the potential capability of apo-lactoferrin to act against harmful bacteria. Overall, this work unveils an understanding at a molecular level regarding the structural changes of the aforementioned proteins that maybe beneficial for future advancement of nutraceuticals.

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. With respect to viral replication, the papain-like (PLpro) and main proteases (Mpro), are critical for processing viral replicase polypeptides. Further, the PLpro possesses deubiquitinating activity affecting key signalling pathways, including inhibition of interferon and innate immune antagonism. Therefore, inhibition of PLpro activity with small molecules is an important research direction. Our aim was to focus on identification of potential inhibitors of the protease activity of SARS-CoV-2 PLpro. We investigated 300 small compounds derived predominantly from our OliveNet™ library (222 phenolics) and supplemented with synthetic and dietary compounds with reported antiviral activities. An initial docking screen, using the potent and selective noncovalent PLpro inhibitor, GRL-0617 as a control, enabled a selection of 30 compounds for further analyses. From further in silico analyses, including docking to scenes derived from a publicly available molecular dynamics simulation trajectory (100 μs PDB 6WX4; DESRES-ANTON-11441075), we identified lead compounds for further in vitro evaluation using an enzymatic inhibition assay measuring SARS-CoV-2 PLpro protease activity. Our findings indicate that hypericin possessed inhibition activity, and both rutin and cyanidin-3-O-glucoside resulted in a concentration-dependent inhibition of the PLpro, with activity in the micromolar range. Overall, hypericin, rutin, and cyanidin-3-O-glucoside can be considered lead compounds requiring further characterisation for potential antiviral effects in appropriate model systems., Graphical abstract Image 1

The SARS-CoV-2 papain-like protease (PLpro) 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 PLpro in complex with interferon-stimulated gene 15 (ISG15) and lysine 48 (K48)-linked diubiquitin were utilised. To predict whether compounds could potentially interfere with the binding of these cellular modifiers, docking was conducted in the absence and presence of ISG15 and K48-linked diubiquitin.

Graphical abstract, The COVID-19 pandemic caused by SARS-CoV-2 has resulted in an international health emergency. The SARS-CoV-2 nsp16 is an S-adenosyl-L-methionine (SAM)-dependent methyltransferase, and with its cofactor nsp10, is responsible for RNA cap formation. This study aimed to identify small molecules binding to the SAM-binding site of the nsp10-nsp16 heterodimer for potential inhibition of methyltransferase activity. By screening a library of 300 compounds, 30 compounds were selected based on binding scores, side-effects, and availability. Following more advanced docking, six potential lead compounds were further investigated using molecular dynamics simulations. This revealed the dietary compound oleuropein as a potential methyltransferase inhibitor.

Although olive oil polyphenols are minor components of olive oil, they contribute substantially to the numerous health benefits of olive oil including against cancer, diabetes, osteoporosis, cardiovascular, and neurodegenerative disease. Studies describing these effects including some mechanisms of action are summarized, as well as details about clinical trials related to promising polyphenols. The powerful antioxidants, hydroxytyrosol and oleuropein, are the focus of this chapter and have been the focus of various health-related studies on olive oil polyphenols that have reported antiinflammatory effects, and other health benefits including enhanced wound healing, and increased digestive and respiratory health. Many of the studies selected for this synopsis involve bioactivities of orally administered olive oil polyphenols to provide further support for the identification of olive oil as a functional food. We propose that more clinical trials are needed to further emphasize the importance of incorporating olive oil or polyphenol supplements into a healthy diet.

According to the World Health Organisation, 70% of all deaths globally can be attributed to chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, respiratory conditions, cardiovascular diseases, diabetes and cancer. Chronic inflammation has a significant impact on the quality of life of affected individuals with an increased risk of developing other chronic inflammatory diseases. Given the limitations of current pharmaceuticals, there is an intense research interest in identifying novel dietary interventions that can regulate and alleviate inflammation. A diet rich in cruciferous vegetables has been extensively studied for its immediate and long-term health benefits, particularly in the context of cardiovascular disease and cancer. Cruciferous vegetables contain the precursor glucoraphanin, which is hydrolysed upon consumption to form l-sulforaphane (LSF), the primary active compound that mediates potential cardio-protective and anti-carcinogenic effects. LSF has been shown to have beneficial effects in vitro and in animal studies through its classical antioxidant and anti-inflammatory properties, and more recently its chromatin modifying effects. This review discusses the clinical evidence to date in relation to the use of LSF in the context of chronic inflammatory diseases as well as provide key mechanistic insights for these effects.