Journal of Biomolecular Structure & Dynamics最新文献

Enterococcus faecalis is commonly found in the GI tract of humans and animals. It causes various infections, especially in hospital environments, and shows growing antibiotic resistance. This study utilized a subtractive proteomics approach to find out the potential drug targets in E. faecalis. Unique metabolic pathways were analysed and compared to the host to minimize adverse effects. Among twenty nine pathogenic specific and seventy three host-pathogen common pathways identified using the KEGG database, sixty seven essential proteins were found through the DEG BLAST search. PSORTB predicted that forty cytoplasmic proteins could be suitable as druggable targets. Further analysis identified fourteen proteins with virulence properties using the VFDB BLAST. Among these, seven proteins with more than ten antigenic sites were subjected to DrugBank BLAST, identifying three novel and four existing drug targets. One of the crucial drug targets, MurM, was selected due to its critical role in peptidoglycan biosynthesis. The reason for selecting MurM is crucial for addressing antibiotic resistance, disrupting bacterial cell wall synthesis, and attaining selective antimicrobial activity. MurM belongs to the mixed αβ class with two functional domains. The possible binding site residues of MurM are Trp31, Lys35, Trp38, Arg215, and Tyr219. Virtual screening identified potential lead candidates for MurM, and four were selected based on their physiochemical, pharmacokinetic, and structural properties. This study provides valuable insights into identifying and analysing a potential drug target, the MurM protein, and its inhibitors in E. faecalis V583.

Herpes simplex virus type 2 (HSV-2) represents a significant etiological agent of recurrent and symptomatic genital herpes, which poses considerable risks to public health and the global economy. The cGAS (cyclic GMP-AMP synthase) protein, a pivotal component in the cGAS/STING DNA-sensing pathway, is an appealing target for pharmacological intervention due to its essential function in the immune response against DNA viruses. Recent investigations have indicated that corilagin, a polyphenolic compound derived from plants, exhibits a wide range of antiviral properties. In this study, we utilized molecular docking, molecular dynamics simulations, MM-PBSA analysis and in vitro experiments to explore the binding sites and interaction dynamics of corilagin with the cGAS protein. Our findings illustrated that corilagin formed a greater number of intramolecular hydrogen bonds with the cGAS protein and displayed lower binding energy relative to the original ligand found in the Protein Data Bank (PDB), thereby suggesting its enhanced potency. In vitro assays confirmed that corilagin effectively mitigated the overactivation of the cGAS-STING pathway, alleviated inflammation and inhibited apoptosis in HaCaT cells, thereby demonstrating a therapeutic potential against HSV-2 infection. In summary, corilagin may act as a structural template for further modifications aimed at developing more effective cGAS inhibitors, thereby advancing the treatment of viral infectious diseases.

Many medical conditions are accompanied by severe pain. Acute pain refers to the experience of pain that lasts for only a few hours, whereas chronic pain is the ongoing emergence of pain signals over an extended period. Since ancient times, cannabis has been utilized for medical purposes. This article demonstrates the medicinal importance of cannabinoids through their analgesic and anti-inflammatory activities. Additionally, the mechanisms of cannabinoid-induced analgesia have been interpreted via preclinical investigations in animals. Cannabinoid extracts were formulated into gel and cream at concentrations of 2.5% and 5%. The cannabis cream showed the highest analgesic activity at 5% compared to methyl salicylate as a control. Moreover, cannabis gel produced a comparable anti-inflammatory effect at 5% against the standard diclofenac sodium. Molecular docking studies of all cannabinoids were performed to understand their modes of interaction and binding affinities with the cyclooxygenase II receptor. Additionally, molecular dynamics simulation studies were conducted for for both the ligand-free and cannabidiol-bound cyclooxygenase II to validate the in vivo and molecular docking results. During simulations, the stability of the protein was analyzed using root-mean-square deviation and root-mean-square fluctuation. The study of trajectories of the ligand-free and ligand-bound proteins was assessed using radius of gyration and solvent accessible surface area. Molecular mechanics/generalized Born surface area was used to evaluate the free energies of ligand binding. Dynamic cross-correlation matrix, principal component analysis and free energy landscape characterized the conformational changes and relative energies of them, which shows the existence of two metastable conformations in cyclooxygenase II, one of which is possibly the native state with catalytic activity. In conclusion, the data from this study support the use of medicinal cannabis in the management of pain. To mitigate the suffering of patients experiencing extreme pain, the rational use of cannabis-based drugs merits significant consideration.

Depression is the fourth leading cause of death due to suicides every year according to WHO. Various adverse effects are associated with many of the available antidepressants due to the irreversible nature of these drugs. So, it is worthwhile to explore the natural phytoconstituents as an alternative therapy for the treatment of depression-dependent symptoms. Computational chemistry provides a cost-effective method to explore or develop new therapies for various diseases through in silico studies. In this study, multitargeting antidepressant potential of Camellia sinensis is explored via docking and binding interaction studies with monoamine oxidase-A enzyme, serotonin, and dopamine receptors involved in depression as targets. All the selected phytoconstituents were evaluated for drug-likeliness properties using Swiss ADME. Among all the selected phytoconstituents, Theasinensin, and Theaflavin-3-gallate were found to have best affinities with all the selected targets under investigation and can be considered as promising lead molecules for the development of novel antidepressants. Molecular dynamics simulations assessed the binding affinity of four compounds to Human Monoamine Oxidase A. All compounds showed potential, with Theaflavin-3-gallate and Theasinesin displaying the strongest binding. This suggests their potential for modulating enzyme activity and potential relevance in depression treatment.

Flavoring compounds are natural or synthetic substances that enhance the food flavor. Research studies have demonstrated that flavoring compounds may have biological activities. In food industry, P. aeruginosa dominates spoilage and contamination of food products. Human exposure to P. aeruginosa may lead to serious infections. P. aeruginosa forms complex biofilms with extracellular slime matrix, providing protection against antimicrobial agents. The present study investigates the role of a flavouring food additive, propenyl guaethol (PG) against Pseudomonas aeruginosa biofilms. Our results demonstrate a significant impact of PG on biofilm forming ability, bacterial attachment, and motility phenotypes. The polystyrene tube assay demonstrates notable inhibition of biofilm formation by P. aeruginosa at 50 and 25 µg/ml (p < 0.01). PG showed marked inhibition of biofilms in combination with gentamicin, kanamycin, and streptomycin. Additionally, PG inhibits twitching, swarming, and swimming motility of P. aeruginosa (p < 0.01). Scanning electron microscopy, fluorescent microscopy, and light microscopy showed thinner biofilms with low exopolysaccharide matrix (EPS) in the presence of PG. Moreover, the role of PG was also evaluated using molecular docking and molecular dynamics simulation to understand the interaction of PG with bacterial type-IV pili subunit, PilY1. PG showed favourable interactions and stable complex formation with type-IV pili subunit (PilY1). The present study highlights the antibiofilm properties of PG, suggesting its potential as a biofilm control flavoring compound.

Simplah (SM) and pliek (PL) oils are derived from the traditional fermentation process of coconut meat, a practice in Aceh, Indonesia, for generations. We studied their chemical composition and interactions with proteins linked to atopic dermatitis (AD), causing inflammation and allergies. Gas chromatography-mass spectrometry (GC-MS) analysis of SM and PL from five coconut plantations in Aceh revealed 53 compounds with a similarity index (SI) ≥ 800. Peroxide and iodine values met standards, but moisture and free fatty acid content were slightly high. Phenolic and flavonoid content are correlated with antioxidant activity. Molecular docking showed l-(+)-ascorbic acid 2,6-dihexadecanoate (PN32) had high binding affinity to IL2 (-8.2801 kcal/mol), JNK1 (-9.5087 kcal/mol), TNF-α (-7.1581 kcal/mol), and ERK2 (-7.9420 kcal/mol). PN32 had significant inhibitory activity against JNK1 but lower stability than the control native ligand (CNL). It can be stated that SM and PL have potential as topical anti-inflammatory and immunosuppressive agents in AD.

Aqueous leaf extracts of Boldoa purpurascens are widely used because of their diuretic, natriuretic, antiurolithiatic, anti-inflammatory and antihypertensive properties. The major component of the extract is the flavonoid 4',5-dihydroxy-6,7-methylenedioxyflavonol-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranoside, but it is not known if this compound is responsible for the biological activity. The objective of this work is to develop effective in silico tools that allow predicting the possible activity of the flavonoid aglycone as an inhibitor of metalloproteases that regulate renal fluid excretion. First, a mathematical ligand-based classification model was developed, using an artificial intelligence and machine learning technique of support vector machines to find the relationship between chemical structure and biological activity. This showed good fit of the statistical parameters with an accuracy greater than 90%, offering a priori information of the flavonoid activity. Subsequently, the flavonoid aglycone was docked to the active site of the enzymes thermolysin (PDB: 6YMS), angiotensin-converting enzyme (PDB: 6TT4) and neprilysin (PDB: 6SUK) using the Extra Precision glide method (Glide-XP), showing conformations with binding energies lower than -5 Kcal/mol. In this study, possible interactions were determined at the catalytic site, where the coordination of negatively charged pharmacophoric groups with the zinc atom of these enzymes is observed. Finally, a preliminary in vivo evaluation was carried out using a diuresis-natriuresis model with sodium quantification in urine which revealed good activity profiles. These results are in correspondence with the ethnopharmacological use of the plant as a diuretic-natriuretic and for the treatment of hypertension.

Xylobiohydrolase plays a crucial role in the hydrolysis of xylan, a complex polysaccharide present in the cell walls of plants. This study focuses on the solution structure and substrate binding analysis of a novel xylobiohydrolase, AcGH30A, from Acetivibrio clariflavus. Secondary structure analysis of AcGH30A in an aqueous environment using Circular Dichroism and in silico modeling revealed an α/β/α sandwich structure with a central β-barrel comprising eight β-strands. Superposition of the homology-modelled structure of AcGH30A with its closest homolog showed that the active-site contains Glu175 and Glu268 as the catalytic residues. Molecular docking confirmed xylobiose as the preferred ligand, showcasing polar interactions with the catalytic amino acids, indicating its xylobiohydrolase activity. AcGH30A displayed a high binding affinity with xylobiose with an association constant (K_a) of 7.83 × 10⁵ M^-1, as determined by isothermal titration calorimetry. Molecular dynamics (MD) simulations of AcGH30A and AcGH30A-xylobiose complex in solution showed reduced RMSD, R_g and SASA values, confirming the stability and compactness of the complex. MD simulations further highlighted the crucial role of Glu175 in hydrogen bonding with the ligand, which acts as an acid or base. Small-angle X-ray scattering (SAXS) analysis of AcGH30A showed its molecular shape as an earbud with a globular structure existing in a monodispersed state, which was corroborated by dynamic light scattering (DLS). The hydrodynamic radius (R_h) of AcGH30A, determined by DLS, was 3.7 nm. This study significantly contributed valuable insights into the structure and functional aspects of AcGH30A.

Phospholipase A₂ (PLA₂) have various inflammatory responses by catalysing the release of arachidonic acid and lysophospholipids from membrane phospholipids. Amongst PLA₂ variants, cytosolic PLA₂ (cPLA₂) is central to inflammation, while phospholipase C (PLC) is involved in macrophage-mediated inflammation, significant in various infectious diseases and cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to prevent inflammation by inhibiting COX 1 and COX 2 enzymes but have several side effects. They affect the gastric mucosa wall, causing stomach and duodenal ulcers. This necessitates desirable alternative enzymes inhibitor with less side effects. In the present study, 57 phytochemicals possessing PLA₂ inhibiting properties were screened and compared with chemically synthesised Varespladib. Based on pharmacological activity as analysed from Way2Drugs server, p-Coumaric acid suited best phytochemical against PLA₂ and PLC. Molecular docking using HADDOCK server for p-Coumaric acid and reference compound Varespladib exhibited binding score of -51.3 ± 1.4 and -32.3 ± 1.5 with PLA₂ respectively whereas displayed binding score of -55.6 ± 3.2 and -31.4 ± 1.3 respectively with PLC. Further, the fact was validated by a comparative 250 ns molecular dynamics (MD) simulation using the Desmond package and MM-GBSA experiments were carried out to analyse the thermodynamic nature of receptor-ligand complex. The MD simulation showed that the phytochemical p-Coumaric acid exhibited strong interactions with cPLA₂ and interacted moderately with PLC during the simulation. However, the reference molecule Varespladib was observed to be interacted strongly with cPLA₂ and feebly with the PLC. This is the first report on the strong efficacy of p-Coumaric acid against cPLA₂.