Journal of Biomolecular Structure & Dynamics最新文献

The current work investigated biocomputational methodologies for α-glucosidase inhibition to examine the antidiabetic potential of methanolic extract of T. mysorensis leaves (MeL). MeL intensely impeded yeast-glucosidase, which is vital for treating postprandial hyperglycemia (IC₅₀ = 5.76 ± 0.10 μg/mL) in comparison to an acarbose control (IC₅₀ = 7.98 ± 0.23 μg/mL). The MeL is affected by phytochemical profiling employing LC-MS, GC-MS, and HPLC analysis to determine the bioactive components responsible for the antidiabetic activity. The specified phytocompounds were employed in silico research following the bioactive profiling, where they were docked into the inhibitor binding site of α-glucosidase. Molecular docking simulations, molecular dynamics simulations, and binding free energy inquiries were utilized in silico research to clarify the mechanism by which T. mysorensis phytocompounds block α-glucosidase. Alangimarckine is a glucocorticoid that is used to treat nasal symptoms. Alangimarckine inhibited the target enzyme with greater binding efficiency (-9.7 kcal/mol) than the acarbose control (-8.6 kcal/mol) during molecular docking. Concerning molecular dynamics simulation studies, Alangimarckine-α-glucosidase complex was found to be stable inside the inhibitor binding site of the protein, compared to the acarbose -α-glucosidase complex. Additionally, alangimarckine inhibited α-glucosidase at IC₅₀ = 5.32 ± 0.19 μg/mL during in vitro inhibition of α-glucosidase, which was efficient in comparison to both MeL and acarbose. Therefore, our research suggests that alangimarckine and MeL from T. mysorensis may function as potent antidiabetic medications. Alangimarckine could be used in in vivo and clinical investigations to specify its antidiabetic properties that target α-glucosidase inhibition.

Viral infections in plants are a big threat to agriculture and the economy. Though the viral infection mechanism is well documented, the cell-to-cell trafficking of the virus is poorly understood. The plant virus is known to encode movement protein (MP) for trafficking the virus from an infected cell to a healthy cell. The movement protein is known to increase plant cells' size exclusion limit (SEL) of plasmodesmata (PD). However, the exact mechanism of the viral trafficking remained unclear. In this study, we proposed a possible mechanism of viral trafficking by using Sesbania mosaic virus (SeMV) as a model system. The movement protein and RNA-dependent RNA polymerase (RdRp) of SeMV were modeled using the ab initio method. It is also known that MP binds with VPg in the movement process and RdRp requires P10 for replication. The models of VPg and P10 were extracted from the structure of polyprotein 2a. The complexes MP-VPg and RdRp-P10 were built with the help of molecular docking and were subjected to molecular dynamic simulation to get stable complexes. The trafficking complex (MP+VPg + RdRp + P10) was obtained by performing the molecular docking of these two complexes. Through MDS, the stability of the trafficking complex was confirmed. For the first time, a trafficking complex was proposed to understand its role in navigation of the viral complex through the host's plasmodesmata.

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.

The Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species are ciphered as ESKAPE pathogens leading agents for multidrug resistance (MDR) related infections. The current research study used kanamycin nucleotidyltransferase (PDB ID: 1KNY), OXA-24 class D beta-lactamase (PDB ID: 3ZNT), efflux pump proteins as a target to identify potential inhibitor phytochemical for ameliorating antimicrobial resistance caused by ESKAPE pathogens. A total of 61 MDR genes of ESKAPE pathogens were scrutinized phylogenetically and protein-protein interaction (PPIs) analysis were performed. The target proteins for structure-based drug design were culled based on functional partners of efflux pump proteins obtained after PPIs analysis in all ESKAPE pathogens. We deployed a comprehensive sequential filtering approach including high throughput virtual screening of an in-house created bioactive phytochemicals library from the IMPPAT database. First, a molecular docking-based high throughput virtual screening process, followed by meticulous filtering of hits based on binding energy and detailed active-site interaction analysis was performed on each target protein separately. During this stage, native ligands of the target proteins were deployed as a control ligand and for docking protocol validation. These 50 top phytochemicals against both proteins were culled. Then filtration of hits was done based on pharmacokinetics, toxicity and bioactivity of phytochemicals. The retained phytochemicals against each protein were analyzed through density functional theory (DFT) to check potential reactivity. After, analyzing DFT-based energy calculations final lead phytochemicals were selected. The lead phytochemical stability within respective active-site and dynamic behavior was analyzed through molecular dynamic (MD) simulations and principal component analysis (PCA). In this way, diosgenin and paulownin phytochemicals were identified as a lead inhibitor ligand against 1KNY and 3ZNT target receptors, respectively. The 1KNY-diosgenin and 3ZNT-paulownin complexes exhibited binding energies of -8.1 kcal/mol and -9.0 kcal/mol, respectively, forming hydrogen bonds with specific key residues (1KNY-Arg22, Ser105, Thr186) and (3ZNT-Trp221, Tyr 112, Met114) displaying stable dynamic behavior during 100 ns MD simulation, with DFT-based energy gaps of -0.254 52 eV and -0.195 87 eV, respectively, suggesting greater stability compared to control ligands. The diosgenin and paulownin phytochemicals are promising starting natural candidates for drug development against multidrug-resistant infections cure.

Stabilizing G-quadruplex structures through small molecule binding is an important area of research in cancer therapy. Cyclic AMP response element-binding protein 1 (CREB1) is a transcription factor of the CREB family that acts as an oncogene. It governs various roles in cellular processes, including the regulation of genes. CREB1 has guanine-rich regions which can form G-quadruplex (GQ) structures. Flavones are natural compounds with anticancer properties. We have investigated the binding mode and interaction mechanisms of three flavone compounds with the CREB1 GQ (CR-GQ) employing molecular docking and 100 ns molecular dynamics simulations, followed by an umbrella sampling method. The binding free energies estimated from MM-PBSA were -47.95, -107.55 and -98.28 kcal/mol, respectively, for flavone, baicalein and chrysin, showing that baicalein and chrysin bind with lower energy than flavone. Root mean square deviations and root mean square fluctuation values indicate that the GQ DNA-ligand system is stable throughout the simulations. The binding free energies and the estimated minimum values in the potential of mean force suggest that the binding reaction is energetically favourable. The compactness of the complexes is evident from the eigenvector map. Hydrogen bonds, pi-pi interactions and van der Waals interactions are the major driving forces in the complex formation. Among the three flavone compounds, baicalein and chrysin complexes are energetically more favourable than the flavone complex. The studied phytochemicals exhibit pharmacokinetic properties, suggesting their potential as promising drug candidates targeting CR-GQ. This study provides pragmatic data for discovering novel drugs targeting CR-GQ and extends the knowledge in stabilizing GQ structures using small molecules.

Designing small molecule inhibitors that are highly selective for Golgi alpha mannosidase II (GMII) over lysosomal alpha mannosidase (LM) remains crucial for the development of novel anticancer drugs targeting the N-glycosylation pathway. Studies have previously identified an unconserved 'anchor site' in GMII that represents an attractive target for achieving selectivity. In this study we conduct molecular dynamics simulations and free energy calculations of GMII and LM with their natural oligosaccharide substrates to investigate the potential of the anchor site. Our findings reveal that the corresponding N-acetylglucosamine residue remains tightly bound to the anchor site in GMII, helping stabilize overall substrate binding to GMII, while the lack of a similar conserved site in LM allows the substrate to fluctuate more freely. Our simulations also suggest that besides stabilizing the catalytic site mannose for cleavage, the anchor site residue may play a role in facilitating the release of the holding site mannose and its transition to the catalytic site in GMII. Subsequently, free energy calculations reveal that the anchor site N-acetylglucosamine contributes 4.107 kcal/mol to the free energy of binding in GMII, with a significantly smaller contribution of 1.035 kcal/mol in LM. This difference of 3.072 kcal/mol in the free energy of binding represents potential gains in selectivity that could be achieved by targeting the anchor site in GMII. Taken together, these findings provide further evidence on the potential of targeting the anchor site in the design of highly selective GMII inhibitors.

Cressa cretica L. is immensely valuable in pharmacology. Computational approach through network pharmacology has been attempted to understand lead molecules of Cressa and their interactions with multiple targets. The phytochemical components of methanolic extracts of Cressa leaves were identified using GC-MS analysis, revealing 16 compounds. Using the identified lead molecules, target proteins were predicted using SWISS-target prediction and were analyzed using Cytoscape. This led to the identification of 56 candidate protein targets, which were used to construct a network using CytoHubba, Centiscape, MCODE, and KEGG pathways. The STRING network was created using Cytoscape for analyzing protein-protein interactions, and the top 5 genes were chosen from a total of 12 algorithms in CytoHubba. The antioxidant effects of C. cretica were investigated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, which showed an increase in the trend activity of the plant extract with an inhibition percentage of 51.53 ± 0.003%. This was further validated by ferric reducing antioxidant power (FRAP) assay that resulted in an antioxidant activity of 6.64 µg/mL at a high concentration of 500 µg/mL. Molecular docking and simulation were performed to study the interaction of human cyclooxygenase-2 (PDB ID: 5KIR) with Cressa metabolites. 5KIR exhibited a higher interaction with methyl stearate, forming two H-bond interactions with Arg 120 and Tyr 355. Molecular dynamics simulation analysis confirmed the stability of the protein-ligand complex. The network pharmacology analysis of putative proteins obtained from C. cretica revealed that the peroxisome proliferator-activated receptor gamma (PPARG) gene is found in numerous cancer pathways and can be inhibited.

The interaction between diphtheria toxin (DT) and nicotinamide adenine dinucleotide (NAD) is central to DT's enzymatic activity, which involves ADP-ribosylation of eukaryotic elongation factors. This study aims to elucidate how solvent environments influence the thermodynamic and structural properties of the DT-NAD interaction. Using Raman Spectroscopy, and complementary techniques, we analyzed two different DTs, and by using Differential Scanning Calorimetry (DSC) we try to understand DT-NAD binding under varying solvent conditions, including distilled water, phosphate-buffered saline (PBS), and different concentrations of dimethyl sulfoxide (DMSO). Our findings reveal that solvent composition significantly alters the thermal stability and binding dynamics of DT. Notably, DSC data showed distinct shifts in melting temperatures (T_m) and enthalpy changes (ΔH) across solvents, with 100% DMSO disrupting the interaction and causing structural denaturation. This study underscores the critical role of solvent selection in modulating protein-ligand interactions and offers valuable insights into the molecular dynamics of DT. These findings have broad implications for biochemical research and therapeutic applications involving protein stability in diverse environments.

One of the most common causes of dementia in older adults is Alzheimer's disease (AD). Numerous mechanisms, including acetylcholine breakdown, amyloid beta buildup, neurofibrillary tangle accumulation, and inflammation, are involved in the pathogenesis of AD. Different targets have been demonstrated in studies to alleviate the cognitive impairment in AD. In AD, amyloid β impairs phosphatidylinositol-3 (PI3)/Akt signaling, activating GSK-3β. This sequence leads to an increase in the phosphorylation of tau, the creation of neurofibrillary tangles, neuronal death, loss of synapses, and memory impairments, all of which are typical symptoms seen in the brains of individuals with AD. Using network pharmacology, molecular docking, and MD simulations, we have determined that indirubin can selectively interact with glycogen synthase kinase 3 beta (GSK-3β). Traditional Chinese Medicine, including Indigo naturalis, is known to have the ability to control chronic diseases having indirubin as the main phytoconstituent. The binding energy of indirubin was -10.9 kcal/mol, which was better than that of the reference ligand with -9.4 kcal/mol. According to MD simulations, the indirubin-GSK-3β complex remained stable during the simulation, exhibiting an RMSD of 1.90 in comparison to the 2.01 and 2.34 for reference-GSK-3β complex and free protein, respectively. According to our study, indirubin phytoconstituent from Indigo naturalis, targets GSK-3β in AD, additional investigation in the quest for inhibitors of this crucial biological target required further in-vitro/in-vivo experimental validations.

Cancer still represents a global health concern due to its high mortality and morbidity rates. Isatin-and pyrazole-based compounds have recently garnered interest as novel anticancer agents. A series of 15 novel spiroisatin pyranopyrazole derivatives were synthesized. Anticancer potential of synthesized agents against EBC-1, HT-29, A549, and AsPC-1 cell lines, representing cancers of the lung, colon, and pancreas, were evaluated using the MTT assay. The possible molecular mechanism contributing to antiproliferative activities of the most potent compounds was further investigated in silico by using SuperPred web server, a ligand-based tool. Docking and molecular dynamics (MD) simulation studies were carried out to investigate the binding affinity and key interactions of the agents with their predicted target. Among the tested compounds, four cyanide-containing derivatives 6c, 6d, 6f, and 6g with bromobenzyl, chlorobenzyl, p-tButyl benzyl and methylbenzyl moieties on the isatin ring, respectively, displayed the highest antiproliferative effects against all four cell lines. These compounds were particularly effective against EBC-1, and HT-29 cells with IC₅₀ values of 3.3-7.1 and 7.3-10.2 μΜ, respectively, while relatively sparing non-cancer cells. The obtained target prediction results suggested that the growth inhibitory activity of the analyzed analogues could be related to tropomyosin receptor kinase C (TrkC) inhibition. The outcomes of molecular docking and MD simulation demonstrated that the most active agents may interact closely with the active site of the suggested target, further confirming target prediction findings. The findings of this study suggest the potential of spiroisatin pyranopyrazole analogues for further exploration as novel targeted anticancer agents.