Journal of Biomolecular Structure & Dynamics最新文献

Ligand binding to G-quadruplex (G4) structures at human telomeric DNA ends promotes thermal stabilization, disrupting the interaction of the telomerase enzyme, which is found active in 80-85% of cancers and serves as a molecular marker. Anthraquinone compounds are well-known G-quadruplex (G4) binders that inhibit telomerase and induce apoptosis in cancer cells. Our current investigation is based on 1,5-bis[3-(diethylamino)propionamido]anthracene-9,10-dione, a derivative of anthraquinone and its binding characterization with two different human telomeric DNA structures, wHTel26 and HTel22, in the effect of K⁺ and Na⁺ by using an array of biophysical, calorimetry, molecular docking and cell viability assay techniques. Binding constants (K_b) in the range of ∼10⁵-10⁷ M^-1 and stoichiometries of 1:1, 2:1 & 4:1 were obtained from the absorbance, fluorescence, and circular dichroism study. Remarkable hypochromism (55, 97%) and ∼17 nm shift in absorbance, fluorescence quenching (95, 97%), the unaltered value of fluorescence lifetime, restoration of Circular Dichroism bands, absence of ICD band, indicated the external groove binding/binding somewhere at loops. This is also evident in molecular docking results, the ligand binds to groove forming base (G4, G5, G24, T25) and in the vicinity to TTA loop (G14, G15, T17) bases of wHTel26 and HTel22, respectively. Thermal stabilization induced by ligand was found greater in Na⁺ ion (27.5 °C) than (19.1 °C) in K⁺ ion. Ligand caused cell toxicity in MCF-7 cancer cell lines with an IC₅₀ value of ∼8.4 µM. The above findings suggest the ligand, 1,5-bis[3-(diethylamino)propionamido]anthracene-9,10-dione could be a potent anticancer drug candidate and has great therapeutic implications.Binding of disubstituted amido anthraquinone derivative, 1,5-bis[3-(diethylamino)propionamido]anthracene-9,10-dione to human telomere HTel22 antiparallel conformation induced thermal stabilization.

Dihydrofolate reductase (DHFR) has gained significant attention in drug development, primarily due to marked distinctions in its active site among different species. DHFR plays a crucial role in both DNA and amino acid metabolism by facilitating the transfer of monocarbon residues through tetrahydrofolate, which is vital for nucleotide and amino acid synthesis. This considers its potential as a promising target for therapeutic interventions. In this study, our focus was on conducting a virtual screening of phytoconstituents from the IMPPAT2.0 database to identify potential inhibitors of DHFR. The initial criterion involved assessing the binding energy of molecules against DHFR and we screened top 20 compounds ranging energy -13.5 to -11.4 (kcal/Mol) while Pemetrexed disodium bound with less energy -10.2 (kcal/Mol), followed by an analysis of their interactions to identify more effective hits. We prioritized IMPHY007679 (Bismurrayaquinone-A), which displayed a high binding affinity and crucial interaction with DHFR. We also evaluated the drug-like properties and biological activity of IMPHY007679. Furthermore, MD simulation was done, RMSD, RMSF, Rg, SASA, PCA and FEL explore the time-evolution impact of IMPHY007679 comparing it with a reference drug, Pemetrexed disodium. Collectively, our findings suggest that IMPHY007679 recommend further investigation in both in vitro and in vivo settings for its potential in developing anticancer and antibacterial therapies. This compound holds promise as a valuable candidate for advancing drug research and treatment strategies.

This study explores the computational discovery of non-peptide agonists targeting the Glucagon-Like Peptide-1 Receptor (GLP-1R) to enhance the safety of major coronary outcomes in individuals affected by Type 2 Diabetes. The objective is to identify novel compounds that can activate the GLP-1R pathway without the limitations associated with peptide agonists. Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) and mortality, which is attributed to the accumulation of fat in organs, including the heart. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are frequently used to manage T2DM and could potentially offer cardiovascular benefits. Therefore, this study examines non-peptide agonists of GLP-1R to improve coronary safety in type 2 diabetes patients. After rigorous assessments, two standout candidates were identified, with natural compound 12 emerging as the most promising. This study represents a notable advancement in enhancing the management of coronary outcomes among individuals with type 2 diabetes. The computational methodology employed successfully pinpointed potential GLP-1R natural agonists, providing optimism for the development of safer and more effective therapeutic interventions. Although computational methodologies have provided crucial insights, realizing the full potential of these compounds requires extensive experimental investigations, crucial in advancing therapeutic strategies for this critical patient population.

Molecular docking techniques are routinely employed for predicting ligand binding conformations and affinities in the in silico phase of the drug design and development process. In this study, a reliable semiempirical quantum mechanics (SQM) method, PM7, was employed for geometry optimization of top-ranked poses obtained from two widely used docking programs, AutoDock4 and AutoDock Vina. The PDBbind core set (version 2016), which contains high-quality crystal protein - ligand complexes with their corresponding experimental binding affinities, was used as an initial dataset in this research. It was shown that docking pose optimization improves the accuracy of pose predictions and is very useful for the refinement of docked complexes via removing clashes between ligands and proteins. It was also demonstrated that AutoDock Vina achieves a higher sampling power than AutoDock4 in generating accurate ligand poses (RMSD ≤ 2.0 Å), while AutoDock4 exhibits a better ranking power than AutoDock Vina. Finally, a new protocol based on a combination of the results obtained from the two docking programs was proposed for structure-based virtual screening studies, which benefits from the robust sampling abilities of AutoDock Vina and the reliable ranking performance of AutoDock4.

Intrinsically disordered proteins (IDPs) are proteins that do not form uniquely defined three-dimensional (3-D) structures. Experimental research on IDPs is difficult since they go against the traditional protein structure-function paradigm. Although there are several predictors of disorder based on amino acid sequences, but very limited based on the 3-D structures of proteins. Dihedral angles have a significant role in predicting protein structure because they establish a protein's backbone, which, coupled with its side chain, establishes its overall shape. Here, we have carried out atomistic Molecular Dynamics (MD) simulations on four different proteins: one ordered protein (Monellin), two partially disordered proteins (p53-TAD and Amyloid beta (Aβ_1-42) peptide), and one completely disordered protein (Histatin 5). The MD simulation trajectories for the corresponding four proteins were used to conduct dihedral angle (ϕ and ѱ) analysis. Then, the average dihedral angles for each of the residues were calculated and plotted against the residue index. We noticed steep rises or falls in the average ϕ value at certain locations in the plot. These sudden shifts in the average ϕ value reflect the interface between regions of varying degrees of order or disorderness in intrinsically disordered proteins. Using this method, the probable conformer of a protein with a higher degree of disorder can be found among the ensembles of structures sampled during the MD simulations. The results of our study offer new understandings on precisely identifying regions of various degrees of disorder in intrinsically disordered proteins.

The aim of this study was to screen the chemical components of Solanum elaeagnifolium leaves and assess their therapeutic attributes with regard to their antioxidant, antibacterial, and antidiabetic activities. The antidiabetic effects were explored to determine the α-amylase and α-glucosidase inhibitory potential of the leaf extract. To identify the active antidiabetic drugs from the extracts, the GC-MS-screened molecules were docked with diabetes-related proteins using the glide module in the Schrodinger Tool. In addition, molecular dynamics (MD) simulations were performed for 100 ns to evaluate the binding stability of the docked complex using the Desmond module. The ethyl acetate had a significant total phenolic content (TPC), with a value of 79.04 ± 0.98 mg/g GAE. The ethanol extract was tested for its minimum inhibitory concentration (MIC) for its bacteriostatic properties. It suppressed the growth of B. subtilis, E. coli, P. vulgaris, R. equi and S. epidermis at a dosage of 118.75 µg/mL. Moreover, the IC50 values of the ethanol extract were determined to be 17.78 ± 2.38 in the α-amylase and and 27.90 ± 5.02 µg/mL in α-glucosidase. The in-silico investigation revealed that cyclolaudenol achieved docking scores of -7.94 kcal/mol for α-amylase. Likewise, the α-tocopherol achieved the docking scores of -7.41 kcal/mol for glycogen phosphorylase B and -7.21 kcal/mol for phosphorylase kinase. In the MD simulations, the cyclolaudenol and α-tocopherol complexes exhibited consistently stable affinities with diabetic proteins throughout the trajectory. Based on these findings, we conclude that this plant could be a good source for the development of novel antioxidant, antibacterial, and antidiabetic agents.

Antibiotic-resistant microbes have emerged around the world, presenting a risk to health. Plant-derived drugs have become a potential source for the production of antibiotic-resistant drugs and cancer therapies. In this study, we investigated the antibacterial, cytotoxic and antioxidant properties of Acalypha indica and Boerhavia diffusa, and conducted in silico molecular docking experiments against EGFR and VEGFR-2 proteins. The metabolic extract of A. indica inhibited Streptococcus iniae and Staphylococcus sciuri with inhibition zones of 21.66 ± 0.57 mm and 20.33 ± 0.57 mm, respectively. The B. diffusa leaf extract produced inhibition zones of 20.3333 ± 0.5773 mm and 20.33 ± 0.57 mm against Streptococcus iniae and Edwardsiella anguillarum, respectively. A. indica and B. diffusa extracts had toxicities of 162.01 μg/ml and 175.6 μg/ml, respectively. Moreover, B. diffusa (IC₅₀ =154.42 µg/ml) leaf extract exhibited moderately higher antioxidant activity compared with the A. indica (IC₅₀ = 218.97 µg/ml) leaf extract. Multiple interactions were observed at Leu694, Met769 and Leu820 sites for EGFR and at Asp1046 and Cys1045 sites for VEGFR during the molecular docking study. CID-235030, CID-70825 and CID-156619353 had binding energies of -7.6 kJ/mol, -7.5 kJ/mol and -7.6 kJ/mol, respectively, with EGFR protein. VEGFR-2 protein had docking energies of -7.5 kJ/mol, -7.6 kJ/mol and -7.3 kJ/mol, respectively, for CID-6420353, CID-156619353 and CID-70825 compounds. The MD simulation trajectories revealed the hit compound; CID-235030 and EGFR complex, CID-6420353 and VEGFR-2 exhibit stable profile in the root mean square deviation (RMSD), radius of gyration (Rg), solvent accessible surface area (SASA), hydrogen bond and root mean square fluctuation (RMSF) and the binding free energy by MM-PBSA method. This study indicates that methanol extracts of A. indica and B. diffusa may play a crucial role in developing antibiotic-resistant and cancer drugs.

The seed storage proteins of cereal and legumes are the primary source of amino acids which are required for sustaining the nitrogen and carbon demands during germination and growth. Humans derive most of their dietary proteins from storage proteins in form of a wide variety of foods, for consumption. The amino acid content of most of these proteins is biased and the need for this biasness is not understood. The high abundance of proline, glutamine, and cysteine in cereals makes the gluten fraction viscoelastic. The cereal proteins have less charge and legume proteins have more charge on them. Their non-polar amino acid distribution has large variations. These characteristics are strongly responsible for the partial and complete unfolding of several domains of the storage proteins. Many of the storage proteins share a highly conserved structural feature within the cupin superfamily spread across all kingdoms of life. The intrinsically disordered viscoelastic proteins help in making dough which is vital for the quality of bread. Unfolded regions harbor more immunogenic sequences and cause food-related allergies and intolerance. We have discussed these properties in terms of comparison of cereal and legume storage protein sequences and allergy. Our study supports the findings that large disordered regions contain allergen-representative peptides. Interestingly, a high number of allergen-representative peptides were cleavable by digestive enzymes. Furthermore, unfolded storage proteins mimic microbial immunogens to induce a memory immune response. Results findings can be used to guide the understanding of immunological characteristics of storage proteins and may assist in treatment decisions for food allergy.

SARS-CoV-2 viral infection is regulated by the host cell receptors ACE2 and TMPRSS2, and therefore the effect of various natural and synthetic compounds on these receptors has recently been the subject of investigations. Cyclodextrins, naturally occurring polysaccharides derived from starch, are soluble in water and have a hydrophobic cavity at their center enabling them to accommodate small molecules and utilize them as carriers in the food, supplements, and pharmaceutical industries to improve the solubility, stability, and bioavailability of target compounds. In the current study, computational molecular simulations were used to investigate the ability of α-, β- and γ-Cyclodextrins on human cell surface receptors. Cell-based experimental approaches, including expression analyses at mRNA and protein levels and virus replication, were used to assess the effect on receptor expression and virus infection, respectively. We found that none of the three CDs could dock effectively to human cell surface receptor ACE2 and viral protease M^pro (essential for virus replication). On the other hand, α- and β-CD showed strong and stable interactions with TMPRSS2, and the expression of both ACE2 and TMPRSS2 was downregulated at the mRNA and protein levels in cyclodextrin (CD)-treated cells. A cell-based virus replication assay showed ∼20% inhibition by β- and γ-CD. Taken together, the study suggested that (i) downregulation of expression of host cell receptors may not be sufficient to inhibit virus infection (ii) activity of the receptors and virus protein M^pro may play a critical and clinically relevant role, and hence (iii) newly emerging anti-Covid-19 compounds warrant multimodal functional analyses.

The natural flavonol quercetin (Q) is found in many vegetables, fruits, and beverages, and it is known as a strong antioxidant. Its metal ion chelation may increase its antioxidant activity. The present study aims to explore the Co(II), Cu(II), and Zn(II) chelating on the antioxidant effectiveness and severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) main protease (M^pro) inhibitory of quercetin using Density-functional theory (DFT), molecular docking, and molecular dynamics simulations (MD). DFT calculations at the B3LYP/LanL2DZ reveal that the high antioxidant activity of the metal-chelated quercetin complexes is mainly returned to their lower ionization potentials (IPs) compared with the one of the free quercetin. Molecular docking of quercetin and its Co(II), Cu(II), and Zn(II) chelates into the active binding sites of peroxiredoxin 5 and SARS-CoV-2 main protease (M^pro) were performed using Lamarckian Genetic Algorithm method. The docked quercetin and its metal chelates fit well into the binding site of the target proteins, and their binding affinity is strongly influenced by the type of the chelated metals Co(II), Cu(II), and Zn(II), and molar ratio metal: ligand, i.e. 1:2 and 2:1. Further, the binding stability of QZn₂ and QCu₂ in peroxiredoxin 5 and SARS-CoV-2 main protease targets is evaluated using MD simulation conducted for 100 ns simulations at natural room temperature conditions, and the obtained results showed that all chelates remain bound to the ligand binding groove of protein except for 1HD2_QZn₂ complex. Finally, the adsorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of quercetin and cobalt(II)-quercetin (QCo₂(II)) were investigated.