Journal of Biomolecular Structure & Dynamics最新文献

Glioblastoma is one of the most lethal types of Gliomas, and its treatment greatly depends on the stage of its detection. Galactin-3-binding protein (LGALS3BP) serves as a novel circulatory biomarker for detecting glioma at an early stage. This protein is also responsible for metastasis, proliferative signaling, angiogenesis, and immune system evasion in the case of brain tumors. Inhibition of LGALS3BP can help in the reduction of metastasis and progression of the disease. Currently, no effective drug is available that can completely treat glioma. In this study, we have virtually screened the National Cancer Institute (NCI) drug databank to discover potential inhibitors of LGALS3BP. Based on the binding free energy calculations using MMPBSA, three compounds, 627861 (-16.69 kcal/mol), 329090 (-13.66 kcal/mol), and 627855 (-10.01 kcal/mol), were selected as potent inhibitors. 200 ns MD simulation studies further complemented this study. Finally, we recommend three molecules, 627861, 329090, and 627855, can be potential inhibitors of LGAL3SBP. The structural scaffolds of these molecules can also lead to the optimization of better inhibitors of LGALS3BP and be implicated in the therapeutic management of glioma after desired experimental validations.

Humans and other animals are both susceptible to avian influenza virus. The avian influenza (AI) pandemic could be brought on by the appearance of a new, radical AI virus capable of spreading disease and maintaining prolonged human-to-human transmissions. The possibility of an AI pandemic makes it important for public health. Despite efforts to identify a linkage between them, the hierarchical relationship between all the factors that influence the pathophysiology of this disease, the shared biological pathways, and the exact identities of its important triggers are yet unknown. To find shared gene expression profiles and overlapping biological processes, an integrated gene expression meta-analysis was carried out for three independent microarray data of the avian influenza virus. This study found 1284 common differentially expressed genes (DEGs), of which 73 were overexpressed and 119 were under-expressed, analyzed using various packages in the R tool. The extensive biological, functional enrichment and pathway analysis was performed using the EnrichR tool and identified the defence response to the symbiont (GO:0140546), Interferon Alpha/Beta Signaling (R-HSA-909733), and spliceosome as the most enriched terms of biological process and pathways respectively. In a network meta-analysis, ISG15 and RELA were pinpointed as the top hub genes for over and under-expression, respectively. This meta-analysis technique for avian influenza infection highlights important gene profiles and their linked pathways. These findings highlight the value of using meta-analysis to detect novel gene markers that may offer key insight into disease pathogenesis and perhaps pave the way for creating more effective therapeutic approaches.

Histone deacetylases (HDACs) are important epigenetic regulators that modulate the activity of histone and non-histone proteins leading to various cancers. Histone deacetylase 1 (HDAC1) is a member of class 1 HDAC family related to different cancers. However, the nonselective profile of existing HDAC1 inhibitors restricted their clinical utility. Therefore, the identification of new HDAC1 selective inhibitors may be fruitful against cancer therapy. In this present work, a pharmacophore model was built using 60 benzamide-based known HDAC1 selective inhibitors and it was used further to filter the large epigenetic molecular database of small molecules. Further, the 3D-QSAR model was built using the best common pharmacophore hypothesis consisting of higher PLS statistics of R² of 0.89, Q² of 0.83, variance ratio (F) of 65.7 and Pearson-r value of 0.94 revealing the model reliability and its high predictive power. The screened hits of the pharmacophore model were then subjected to molecular docking against HDAC1 to identify high-affinity lead molecules. The top 10 hits were ranked from the docking studies using docking scores for lead optimization. The potential hit molecules M1 and M2 identified from the study showed promising interaction during HDAC1 docking and MD simulation studies with acceptable ADME properties. Also, the newly designed lead compounds M11 and M12 may be considered highly potential inhibitors against HDAC1. The 3D-QSAR analysis, conformational requirements, and observations noticed in the MD simulations study will enable the optimization of lead molecules and to design of novel effective, and selective HDAC1 inhibitors in the future.

The prolific role of bioactive ligands in interacting with a variety of proteins has become a focal point of interest in pharmacokinetics and pharmacodynamics, thus sparking substantial enthusiasm within the realm of medicinal chemistry. The reversible binding of small molecules and proteins is a characteristic feature, and it's essential to investigate these interactions to understand their mode and mechanism of action within the human body. Therefore, the primary objective of the present study is to understand the underlying mechanism by which yohimbine (Yoh) interacts with protein myoglobin (Mb), employing both in silico and in vitro methodologies. The emission spectroscopy studies yielded a binding constant of 10⁵ M^-1 and a binding site ratio of 1:1. The structural perturbation induced in the protein Mb by Yoh was also illustrated by circular dichroism. The results of the molecular docking investigation resulted in numerous significant interactions between Mb and Yoh, indicating a substantial binding affinity. The accuracy of the docking data was further confirmed through the use of molecular dynamics (MD) simulations, which were then followed by principal component analysis and free energy landscape investigations. The study posited that the stability of the Mb-Yoh complex remains intact throughout the simulated duration, exhibiting little alterations in its structural conformation. Therefore, the association between ligand-protein plays a key role in determining circulatory lifetimes and bioavailability. These factors, in turn, are pivotal in the rational drug design process.

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.

Antimicrobial resistance is recognized as a major worldwide public health dilemma in the current century. Pseudomonas aeruginosa, a Gram-negative opportunistic pathogen, causes nosocomial infections like respiratory tract infections, urinary tract infections, dermatitis, and cystic fibrosis. It manifests antibiotic resistance via intrinsic, acquired, and adaptive pathways, where efflux pumps function in the extrusion of antibiotics from the cell. MexB protein, part of the tripartite efflux pumps MexAB-OprM present in P.aeruginosa, expels the penems and β-lactam antibiotics, thereby enhancing Pseudomonas resistance. The current study was intended to screen around 1602 clinically approved drugs to understand their ability to inhibit the MexB protein. Amongst them, the top 5 drug molecules were selected based on the binding energies for analyzing their physio-chemical and toxicity properties. Lomitapide was found to have the maximum negative binding energy followed by Nilotinib, whereas Nilotinib's number of hydrogen bonds was higher than that of Lomitapide. ADMET study revealed that all 5 drug molecules had limited solubility. Also, Lomitapide and Venetoclax showed low bioavailability scores, while Nilotinib, Eltrombopag, and Conivaptan demonstrated higher potential for therapeutic levels. A molecular dynamic simulation study of the 5 drugs against MexB was carried out for 200 nanoseconds. The RMSD, RMSF, Hydrogen bond formation, Radius of gyration, SASA, PCA, DCCM, DSSP and MM-PBSA binding energy calculation along with demonstrated high stability of the MexB-Nilotinib complex with lesser distortions. Our study concludes, that Nilotinib is a potential inhibitor and can be developed as a therapeutic agent against MexB protein for controlling P. aeruginosa infections.

Novel biomedical applications of various nanomaterials are being extensively researched as drug delivery systems. These nanomaterials deliver various anticancer treatments into the specific tumor cell sites, which reduces their terrible side effects. In this study, we have used DFT/B3LYP/6-311++G(d,p) level of theory to examine the efficacy of the pristine B₄₀ fullerene (Boron) as a drug delivery vehicle for gemcitabine an anti-lung cancer medication at various position. From our investigation the most stable adsorption orientation was observed between double bonded oxygen atom of the drug and six membered ring boron atoms of B₄₀ fullerene both in gas and solvent phases. The frontier molecular orbitals and QTAIM studies further support the interaction of gemcitabine medication with the B₄₀ fullerene. NBO and MEP methods show substantial charge transfer from gemcitabine drug molecules to the fullerene. Overall, the results suggest that the B₄₀ fullerene effectively adsorbs the drug and hence can be used as a tool for drug delivery system.

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.

A C-terminal fragment of the adhesion protein Fibulin7 (Fbln7-C) binds to monocytes and neutrophils via integrin α5β1, regulating their adhesion and immunological functions through Erk and STAT signaling pathways. It also inhibits cell binding, spreading, and migration on fibronectin. However, the precise structural components of Fbln7-C that interact with various domains of integrin α5β1 and contribute to its regulatory effects are not entirely understood. This study investigated the structural dynamics of Fibulin7 fragments and the mechanisms by which Fbln7-C regulates α5β1 integrin activation using protein modeling, protein-protein docking, molecular dynamics simulation (MDS), and binding free energy calculations. An energy-minimized model of α5β1 integrin, Fibulin7 full length (Fbln7-FL), and Fbln7-C was developed and validated using 100 ns MDS. Additionally, protein-protein docking was used to confirm Fbln7-C's better integrin binding ability over Fbln7-FL. A 500 ns MDS on the docked Fbln7-C integrin complex revealed the regulatory effects of Fbln7-C on arginine-glycine-aspartic acid (RGD) bound integrin α5β1. The simulation studies showed that Fbln7-C's attachment to activated α5β1 integrin increased the distance between the RGD and its interacting residues on both integrin subunits, shifting the RGD ligand from its original binding position and inactivating the integrin. Further analysis using free energy landscape (FEL), principal component analysis (PCA), and binding energy calculation validated the alteration in α5β1 integrin's structural dynamics following Fbln7-C binding. This could relate to obstruction in the outward swing of the integrin's hybrid domain and result in the low-affinity, inactive headpiece conformation of the α5β1 integrin.

The present study delves into the comprehensive structural investigations of the six Chalcone derivatives (4A-F), each featuring the 1, 2, 3 triazole linkages. The work commences with the synthesis by employing a multifaceted approach to unravel its molecular properties and potential biological significance. Single crystal X-ray diffraction technique was used to determine the precise 3D structure of the grown single crystals of 4D and 4F. The crystal structure exhibited significant investigations on intermolecular interactions, particularly hydrogen bonding, π-π stacking, Van der Waals forces and other intra-intermolecular interactions contributing to the molecular assembly. Density Functional Theory (DFT) was employed using the B3LYP functional and 6-311++ G (d, p) basis set to explore compound's electronic structure and physicochemical properties. Quantum theory of atoms in molecule (QTAIM) and non-covalent interactions (NCI) analysis provided insights into the topology of the compounds. Further the biological assessments were performed to know the antimicrobial properties of the compounds against both gram-negative and gram-positive bacteria. The research also culminated the evaluation of the drug-likeness of the compounds, drawing upon ADME-T predictions. Further, in silico molecular docking and dynamics simulation analysis were conducted to anticipate the most favorable binding configuration of the derivatives within the active site cavity of the Type II topoisomerase DNA gyrase receptors. In vitro antimicrobial study was also performed and it demonstrated notable results. Overall, this extensive study offers a deep study into the structural intricacies of these compounds, providing insights for chemical and biological evaluations, particularly in the context of bacterial enzyme inhibition.