Journal of Biomolecular Structure & Dynamics最新文献

Public health is seriously threatened by the highly pathogenic zoonotic Nipah virus (NIV). Since no effective medicines or vaccines exist, it is imperative to investigate potential therapeutic molecules against NIV. In this research, we concentrated on the G-glycoprotein of NIV as a potential therapeutic target. From seven medicinal plants renowned for their antiviral efficacy against NIV, we created a chemical library with 80 phytocompounds. The compounds were subjected to molecular docking, drug-likeliness properties, and toxicity analysis (ADMET). Based on good docking scores and ADMET properties, we opted for two compounds-Phyllnirurin (CID: 179963) and Diosgenin (CID: 99474). Post-docking analysis and molecular dynamics simulations validated the interactions and stability of the complexes formed between the protein and ligands. Finally, network pharmacology analysis demonstrates that these compounds interact with a wide range of host proteins. Therefore, these two phytocompounds in terms of lead candidates, have the potential to be key players in developing therapies against the Nipah virus, and future experimental validation is required.

Poor bioavailability and reduced stability are the main drawbacks to efficiently utilizing many naturally occurring antioxidants, so their binding to circulatory proteins is essential. This work investigated whether major human circulatory proteins, besides albumin, including transferrin, alpha-2-macroglobulin, and fibrinogen, bind widely consumed antioxidants and food supplements, including quercetin, trans-resveratrol, and dihydrolipoic acid, thus filling the gap of detailed pharmacokinetic properties of these food supplements. Detailed examination of the protein structural and functional changes that occur upon ligand binding was analyzed by spectroscopic methods and in silico docking and molecular dynamic simulation studies on the model that consists of the protein/antioxidant pair with the highest affinity constant. It was found that alpha-2-macroglobulin binds trans-resveratrol with the highest affinity (K_a of 4.5 x 10⁴ M^-1). In silico results revealed four potential binding sites between trans-resveratrol and alpha-2-macroglobulin, with hydrogen bonds being crucial for binding, while other observed interactions (primarily aromatic interactions) are of secondary importance. The binding of trans-resveratrol to alpha-2-macroglobulin leads to mutual protection of both molecules from oxidative stress and significantly increased hidrosolubility of resveratrol, both of which could serve to increase the bioavailability and bioactivity of resveratrol in circulation.

In this paper, we have attempted a theoretical calculation of some plant-isolated compounds as potential inhibitors of oxidative stress and Advanced Glycation Endproducts (AGEs). Herein, theoretical reactivity indices based on the CDFT theory were computed to explore the reactivity of five isolated products from Calophyllum flavoramulum. Global reactivity indices based on HOMO and LUMO energy such as electronic chemical potential, hardness, electrophilicity and the local reactivity descriptors Parr function, molecular electrostatic potentials(MEP), electrostatic potential (ESP) and thermodynamic parameters for the studied compounds are computed and discussed using DFT method and two functionals B3LYP and CAM-B3LYP with 6-31 G(d,p) basis set. The free radical scavenging activity mechanisms (HAT, SET-PT, and SPLET) of some of the isolated products with DPPH are also presented in this work. SET-PT mechanism of the antiradical activity is found to be thermodynamically favorable. Furthermore, a molecular docking study with RAGE receptor and AtGSTF2 enzyme was conducted, in which flavonoids 4 and 5 show a low binding affinity with -8.42 and -10.49 kcal/mol for RAGE, -8.67 and -9.00 kcal/mol for AtGSTF2. After the encouraging outcomes from the molecular docking study, the 4-AtGSTF2 and 5-RAGE complex were subjected to 200 ns molecular dynamics simulation using Desmond, where both studied systems exhibited remarkable stability throughout the 200 ns simulations. Also, the MM-GBSA method was measured by calculating the binding free energy using the individual energy components. Finally, the ADMET predictions were assessed to anticipate the behavior of a drug candidate within the human body.

Monoamine oxidase (MAO) is crucial for the breakdown of monoamine neurotransmitters, making it a promising target for treating neurodegenerative disorders, such as depression, Alzheimer's disease, and Parkinson's disease. In this study, we investigated the selective inhibitory activity of chromone-based compounds against MAO-A and MAO-B for neurodegenerative disease treatment. In literary sources, thirty chromone derivatives have been identified as potential ligands for MAO-A and MAO-B inhibitors. We utilized molecular docking to evaluate how the most active compound interacted with the targeted MAO-A and MAO-B. Compound 2 g, the most active for MAO-A, demonstrated a lower CDOCKER energy compared to the co-crystallized ligand. Meanwhile, compound 2f, the most active for MAO-B, showed a CDOCKER energy similar to the co-crystallized ligand and exhibited similar binding patterns. Furthermore, we constructed a quantitative structure-activity relationship (QSAR) model to predict the properties and estimate IC₅₀ values for 30 chromone derivatives functioning as MAO-A and MAO-B inhibitors. The model predictions were validated against experimental measurements. Our 2D QSAR model demonstrated robustness, with a statistically significant non-cross-validated coefficient (r² < 0.9), cross-validated correlation coefficient (q² < 0.6), and predictive squared correlation coefficient (r²_pred < 0.8). Additionally, MD simulations confirmed the stable binding of compounds 2 g and 2f with MAO-A and MAO-B, respectively, displaying substantial binding energy. The most effective pharmacophore model identified key features, such as hydrogen bond acceptors and hydrophobic interactions, that contribute significantly to inhibitory potency. This study offers valuable insight into the selection of compounds with improved selectivity for MAO inhibition.

The present study examined the vascular effects of peppermint or mint (Mentha longifolia L.) using an abdominal aortic rings model. Concentration-response curves for mint oil were generated after precontracting isolated mouse aorta with phenylephrine. The effect of different receptor antagonists and ion channel or enzyme inhibitors on the vasorelaxant potential of mint oil were studied. Molecular docking studies were conducted using computational techniques to investigate the potential interactions between the bioactive constituents of mint oil and key vascular targets. The tension of aortic rings, which had been contracted by phenylephrine, relaxed as a function of the concentration of mint oil (0.0002-2 mg/mL). Pretreatment of the rings with the nitric oxide synthase inhibitor (L-NAME), a nonselective β-blocker (propranolol), and a muscarinic receptor blocker (atropine) didn't show significant resistance to the vasodilatory effects of the mint oil. The vasodilatory effects of mint oil were significantly diminished when the rings were pretreated with glibenclamide, an inhibitor of ATP-sensitive K⁺ channels. In addition, indomethacin, a cyclooxygenase (COX) inhibitor, did influence mint oil's tension in the preparations precontracted with phenylephrine. The present findings imply that ATP-sensitive K⁺ channels activation, blocking of Ca²⁺ channels, and inhibition of COX play a role in mediating the mint oil-induced vasorelaxation. Molecular docking studies of mint oil constituents showed that β-Elemene and Aromadendrene can interact with K⁺ and Ca²⁺ channels through various hydrophobic interactions with key amino acid residues. Additional work is needed to confirm the possible beneficial application of mint oil or its constituents in regulating the vascular tone.

The complex cell envelope of pathogenic mycobacteria provides a strong barrier against the host immune system and various antibiotics. Phosphatidyl-myo-inositol mannosides (PIMs), lipomannan (LM), and lipoarabinomannan (LAM) are structurally important elements of mycobacterial cell envelope and also play crucial roles in modulating the host immune functions. At the cytoplasmic side of the mycobacterial inner membrane, phosphatidyl-myo-inositol (PI) is mannosylated by α-mannosyltransferases PimA and PimB' to synthesize PIM₂ using GDP-mannose (GDPM) as the mannose donor. This PIM₂ compound is acylated to synthesize Ac_1/2PIM₂, which is further mannosylated by an unknown enzyme PimC to produce Ac_1/2PIM₃. Synthesis of LM/LAM or higher PIM compounds (Ac_1/2PIM₄ / Ac_1/2PIM₅ / Ac_1/2PIM₆) requires polyprenol-phosphate-mannose (PPM) as the mannose donor and takes place at the periplasmic side of the mycobacterial inner membrane. Previously, a GDPM-dependent α-mannosyltransferase RvD2-ORF1 was identified as the PimC in Mycobacterium tuberculosis CDC1551 (Mtb CDC1551). However, its counterpart was missing in most other mycobacterial strains. Bioinformatic analyses, molecular docking, and molecular dynamics (MD) simulations in this study indicate that Rv0225, an essential protein of Mycobacterium tuberculosis H37Rv, is a GDPM-binding α-mannosyltransferase. The predicted structure of Rv0225 showed similarities with mycobacterial proteins PimA, PimB', and PimC of Mtb CDC1551. Further molecular docking and MD simulations also suggest that Ac_1/2PIM₂ can bind to Rv0225 and showed similar dynamic patterns as the glycolipid substrates of PimA and PimB'. The binding of Ac₁PIM₃ caused opening and closing motions of Rv0225, a phenomenon also observed in the case of PimA. Overall, the computational analyses suggest that Rv0225 may play the role of PimC in mycobacteria.

Selective inhibition of histone deacetylase 8 (HDAC8) has emerged as a promising approach for treating various diseases, including cancer. However, finding key structural features for HDAC8 inhibition and developing effective and selective HDAC8 inhibitors (HDAC8is) pose significant challenges. In the past few years, the development of various scaffolds for inhibiting HDAC8 has significantly risen and the quest continues. In such cases, N-heterocyclic derivatives (such as thiazine, indole/pyrrole, pyrazole, triazole, indole, etc.) can play a crucial role in the discovery of novel selective HDAC8 inhibitors. In this current work, Bayesian and SARpy QSAR models were established on a structurally diverse set of 188 selective HDAC8 inhibitors after an extensive literature search. QSAR modelling suggests N-heterocyclic rings as important structural fingerprints for selective as well as promising HDAC8 inhibition. Further, molecular docking and molecular dynamics (MD) simulation studies were carried out on selected compounds (4, 15, 36, 40, and 188) containing N-heterocyclic rings to emphasize the significance of these scaffolds in HDAC8 potency. In addition to this, toxicity studies were carried out using density functional theory (DFT) to determine the toxicity profile of investigated compounds which indicated that the compounds are non-toxic. The outcomes of this research will aid in the exploration of certain key directions for the selective HDAC8 inhibitor design that could speed up the search for anticancer drugs.

Spectroscopic and molecular simulation techniques are increasingly becoming powerful tools for studying the drug-protein binding acting. In this article, the conjugation features of palbociclib, a cell cycle-dependent kinase 4/6 (CDK4/6) inhibitor primarily used for HR+/HER2- breast cancer treatment, with bovine serum albumin (BSA) was examined in a physiomimetic setting. Based on the experimental results, the incorporation of a 1:1 palbociclib-BSA complex resulted in the intrinsic fluorescence quenching of BSA by palbociclib via static quenching. The results of competition experiments suggested that palbociclib has a higher probability for entering the BSA target Site III as compared to site I and site II. The thermodynamic and competition experiments yielded evidence to suggest that van der Waals forces, hydrogen bonding and hydrophobic interactions were responsible for the binding of palbociclib to BSA. Structural alterations resulting from palbociclib administration to BSA illustrated a minor influence of palbociclib on the advanced conformations of BSA. However, it led to an increase in hydrophobicity surrounding the tryptophan (Trp) and tyrosine (Tyr) residues. In addition, the experimental findings underwent a validation via the application of molecular docking and molecular dynamics simulations.

Molecular dynamics computer simulation of intramolecular amino acids and oligomers of glycine, diphenylalanine, and tryptophan vibrations in an electric field with planar and rotational polarization at THz - IR frequency range is implemented for the first time. The development of the method consists in obtaining amplitude-time realizations of electric dipole moment and Fourier frequencies of intramolecular vibration with the help of supercomputer modeling. Effects of spectral components in the far and middle IR ranges are identified, revealing novel aspects of physical properties and transformations. The obtained data can be used in life sciences, medical, pharmaceutical, and nano-biomolecular technologies, as well as in bioelectronic and heterogeneous hybrid microelectronic devices with embedded biomolecular components.

It is concerning that allergic symptoms related to consuming black gram or Vigna mungo-based diets have been reported from Asia and Australia. Since the identification of specific allergenic proteins from blackgram is in its infancy, it demands further exploration and underscores the complexity of food allergies. To decipher allergenic proteins from V. mungo and to characterize them, an in-silico study was conducted. Out of the total proteins available on UniProt, the potential allergens, vignain (P12412), peptide-prolyl cis-trans isomerase (D3VMM4), and cysteine protease (Q9MB27) were selected for further analysis based on their allergenic potential. Their antigen binding sites were predicted and 3D structures were modeled and docked with immunoglobin IgE and T cell antibody and their binding energies were obtained. To find the stability of the interactions, MD simulations were conducted and the results indicated that Q9MB27, D3VMM4 and P12412 formed stable bonds with IgE and T cell antibodies. Identifying the specific proteins responsible for these allergic reactions could be crucial for developing effective diagnostic tools and potential therapies to help individuals manage their allergies more efficiently. Further validation of the above results by in vitro and in vivo methods is highly recommended.