Journal of Biomolecular Structure & Dynamics最新文献

Antimicrobial peptides (AMPs) are majorly utilized by the hosts to clear off the invading bacterial pathogens. The AMPs help in the clearance of bacterial pathogens primarily by disrupting their membrane homeostasis. However, most Gram-negative pathogens have developed multiple machineries, enabling them to resist the action of AMPs. One such machinery is the sensitivity to the antimicrobial peptides (Sap) transport system. The Sap system belongs to the ATP-binding cassette (ABC) transporters and consists of five components, viz. SapABCDF. It is reported that it uptakes AMPs inside the cell that are proteolytically degraded by proteases. In contrast, in Escherichia coli, the Sap (EcSap) transport system was suggested as a putrescine exporter. In this study, with the aid of computational biological approaches, the functional prospects of the EcSap transporter were investigated. The results of this study suggest that the protein EcSapA can bind dipeptides having aromatic amino acids. Further, it can bind to oligopeptides, including AMPs. AMPs such as protamine and protegrin-1 show binding to the protein EcSapA. In addition, the molecule heme shows binding affinity toward the protein EcSapA. In summary, EcSapA seems to be involved in the uptake of a wide range of molecules, such as dipeptides, AMPs and heme. The results of this study can be utilized to design inhibitors targeting the protein SapA, as inhibiting this protein may render the bacterial system sensitive to the attacking AMPs, hence allowing the host machinery to clear off the invading pathogen.

Leishmaniasis, a neglected tropical disease affecting 0.7 to 1.3 million people annually, has only a few toxic therapeutic options. This study describes the synthesis, structural characterization, in silico and in vitro assessment of novel thiosemicarbazones of coumarin incorporated isatins (6a-6m) as highly as potent and safe antileishmanial agents. Molecular docking was initially used to determine the binding of these compounds to the active cavity of the target protein (Leishmanolysin gp63) of Leishmania (L.) tropica. Among all the docked compounds, three 6d, 6f and 6l showed high binding affinities due to strong H-bonds and hydrophobic π-interactions. Importantly, the in vitro investigations of thirteen synthesized compounds for antileishmanial activity against L. tropica promastigotes and axenic amastigotes, complemented the docking results. The compound 6d was found to be the most active of the series at micromolar concentrations both against promastigotes (IC₅₀ = 2.985 μmol/L) and axenic amastigotes (IC₅₀ = 13.46 μmol/L) in comparison to the tarter emetic (IC₅₀ = 12.56 μmol/L) and amphotericin B (IC₅₀ = 1.826 μmol/L), respectively. Significantly, all active compounds are much less toxic as compared to the positive control (Triton X-100) and, tartar emetic (TA) and amphotericin B when screened for their toxicity against human erythrocytes. To gain further insight into the interaction dynamics of our target protein on binding with compound 6d, molecular dynamic simulation was performed for a course of 100 ns for both the apo-protein and the protein-ligand complex. The results revealed consistent structural stability for the protein-ligand complex, aligning with characteristics seen in the apo-proteins.

Antibiotic resistance, a critical global health concern, arises as bacteria and other microbes evolve to resist drugs. The AcrB protein, a key component of the AcrAB-TolC multidrug efflux pump in Escherichia coli, plays a significant role in antibiotic resistance and presents an opportunity for new drug development. Inhibiting this pump has the potential to reverse antibiotic resistance and restore drug efficacy. This study explores potential molecules that target the AcrB protein as a novel therapeutic strategy against multidrug-resistant (MDR) Gram-negative bacteria, utilizing in-silico techniques. The initial step in the selection of ligands involved gathering compounds from the PubChem database that are structurally similar to erythromycin A, with a cutoff score of 80 or higher in the similarity search. Stringent drug-likeness criteria were applied, yielding 111 compounds that share structural similarities with erythromycin A. Virtual screening against the target protein identified 72 compounds with promising docking scores between -6.13 and -3.06 kcal/mol using the MtiOpenScreen web server. Subsequently, four compounds (CID:102055530, CID:101369593, CID:139312504, and CID:143044924), along with the control compound (erythromycin A), were selected for further analysis. These analyses included re-docking, molecular dynamics simulations, free binding energy calculations, and PCA-based free energy landscape investigation. The findings suggest that the identified compounds could serve as foundations for developing new inhibitors targeting the AcrB protein, offering a promising strategy to counteract bacterial resistance. This research supports the need for further experimental validation to confirm these in-silico predictions and to potentially advance these compounds through the drug development process.

Marburg viruses (MARV) are negative-stranded RNA viruses belonging to filoviridae family. This virus causes severe haemorrhagic fever in humans and non-human primates, with a high fatality rate. Currently, there are no vaccines or drugs have been approved to induce productive immunity or control viral infection. As a result, vaccination against this virus is essential for reducing mortality rates. The current study aimed to identify CTL (cytotoxic T lymphocytes) and B-cell epitopes of MARV using in silico tools. A total of 3697 CTL epitopes and 4577 B-cell epitopes were predicted in the viral proteome of MARV. A reverse vaccinology approach was used to reduce the predicted CTL epitopes by adjusting MHC class I processing, immunogenicity, and other parameters. Finally, epitopes that are non-toxic, antigenic, non-allergenic, and non-homologous to the human proteome were chosen. Among these, 29 novel immunodominant MARV CTL epitopes were docked to their respective HLA alleles and the stability of the interaction was assessed using molecular dynamics simulation. All HLA-epitope complexes were found to be stable indicating that the predicted epitopes are binding with good affinity. Finally, a multi-epitope vaccine with three B-cell epitopes and ten CTL epitopes was designed. The secondary and tertiary structures of the vaccine construct were predicted, refined, and validated. The vaccine construct's codons were then optimized for maximum protein expression. In silico cloning was used to insert the gene construct into the pcDNA 3.1 (+) vector. This final construct can be used to develop an effective epitope-based MARV vaccine.

Due to the poor bioavailability of Cefuroxime axetil, the current study explored the synthesis of complexes of a Cefuroxime axetil with metal ions thereby increasing their biological activities. This structural modification on the one hand solves the solubility problem and on the other hand may tend to improve the pharmacology, toxicology, and other physio-chemical properties of the drug. Cefuroxime-loaded metal complexes (1-6) of CrBr₃.6H₂O, CoCl₂.6H₂O, CuCl₂, MnCl₂.H₂O, NiCl₂.H₂O, and ZnCl₂ were synthesized in equimolar ratios where the drug acts as a bis-bidentate ligand. These complexes were characterized by using UV-Vis, FT-IR, and TGA. The synthesized metal complexes were subjected to enzyme inhibition assay targeting β-glucosidase. The Cefuroxime-copper (II) complex was found to be 5 times more active as compared to the free ligand, and almost 1.2 times more active compared to the standard drug. The binding energy of a ligand with a metal ion provides insight into the complicated molecular processes involved in the binding of protein-metal complexes through in-silico study. The criteria set forth for the confirmation were binding energy ΔG, and root mean square deviation using MoE software. Molecular docking study reveals the binding energy of ligands with metal ions. MD simulations unveiled a robust binding affinity between the inhibitors and the active site of β-glucosidase, inducing notable structural conformational alterations within the protein. Conclusively, These metal complexes have a greater capacity to block β-glucosidase activity than standard drugs, as evidenced by their binding energy and interaction pattern inside the active pocket, making them a better drug candidate.

The potential health risks associated with radionuclides, particularly actinides, have prompted investigations into their interactions with body fluids in living organisms. Human serum albumin (HSA), a plenteous plasma protein with extraordinary binding capacities, is a key player in these interactions. The present study is intended at understanding the interplay between metal ions, namely, zinc and uranyl ions and fatty acids binding with HSA, using all atom equilibrium and non-equilibrium molecular dynamics simulations. Results highlight distinct behaviours of zinc and uranyl ions, elucidating how their interactions with HSA are influenced by the presence of fatty acids. Hydrogen bonding dynamics analysis reveals the disruption of existing bonds due to fatty acid binding, contrasting with the weakening effect caused by metal binding. The resulting conformational changes have significant implications for HSA's structure and dynamics. The potential of mean force (PMF) plots reveals binding and unbinding routes for zinc and uranyl ions, both in fatty acid's presence and absence. Short-range interactions reveal distinct binding behaviours of zinc and uranyl ions, altered by fatty acids, providing insights into unbinding pathways and correlating with the PMF plots.

Cold plasma treatment is a revolutionary technique that is used in industry to sterilize food and materials. The Cold Plasma mechanism relies on producing reactive oxygen species, but it also has disadvantages for biological materials. To prevent any negative effects, it is crucial to preserve protein stability during Cold plasma treatment. This research assessed the effects of cold plasma treatment on BSA in 30s, 60s, 120s, and 180s. Curcumin has been tested to assess its protective function against structural changes in proteins during cold plasma treatment. The effect of cold plasma on the structural changes of BSA in the presence and absence of curcumin were evaluated using UV-visible spectroscopy, autofluorescence spectroscopy, ANS fluorescence spectroscopy, ATR-FTIR spectroscopy, thermal aggregation assay, and DPPH assay. Further investigation has been carried out by conducting molecular dynamic simulation. Curcumin, an antioxidant, has been shown to reduce structural changes in proteins when treated with cold plasma, according to our study. Curcumin in food sterilization process by cold plasma can be used to prevent protein content changes.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are important target proteins to treat cognitive dysfunction in neurodegenerative diseases, such as Alzheimer's disease and Parkinson disease. Hence identification of inhibitors against these proteins is ever-growing. To get a foresight on the potential of a molecule that could be forwarded as a drug candidate, the combinations of bioinformatics [including molecular docking and molecular dynamics (MD) simulation], computer-assisted-theoretical analysis and in vitro strategy were employed to gain knowledge on interaction/inhibition of newly synthesized ester of plumbagin (PLU) and indole-3-propionic acid (IPA) called PLU-IPA with/against AChE and BChE. Density functional theory and ADME analysis revealed the non-toxicity and chemical reactivity gained by the molecule due to esterification and drug-likeness of PLU-IPA. PLU-IPA inhibited AChE and BChE in micromolar concentration through non-competitive mode. In molecular docking, PLU-IPA interacted with amino acids present in sub-pockets near the catalytic site, anionic site, and PAS of electric eel AChE (eAChE), human AChE (hAChE), and hBChE. Through computer-assisted-theoretical analysis, the importance of non-covalent interactions for the proper orientation of PLU-IPA within the active site gorge of AChE/BChE was understood. Further MD simulation results also confirmed the stable interaction of PLU-IPA with AChE/BChE.

The objective of this study was to isolate and characterize a cytotoxic compound from the hydromethanolic extract of Dalbergia sissoo Roxb. ex DC. leaves using the cold percolation technique. Thin-layer chromatography was employed to isolate the cytotoxic component from the crude plant extract, and its cytotoxicity against lung adenocarcinoma (A549) cells was evaluated using the MTT assay. The structure of the isolated cytotoxic compound was determined through FTIR, NMR, UV analysis, and LC-MS/MS methods. Through comprehensive characterization, a cytotoxic compound called Biochanin A (BA) was identified, exhibiting significant anticancer activity with an IC₅₀ value of 21.92 ± 2.19 μM against A549 cells, while demonstrating lower cytotoxicity towards normal lung cells (WI-38) with an IC₅₀ value of 285.12 ± 2.19 μM. Notably, BA induced morphological changes in A549 cells, leading to apoptotic alterations and the generation of reactive oxygen species (ROS), as confirmed by multiple techniques (AO/EB, DAPI, Giemsa). In silico molecular docking, ADMET, MMGBSA, and molecular dynamics simulation investigations support the RT-PCR and cell biology findings. As a result, BA's molecular mechanism of action involves ROS-induced apoptosis mediated by caspases 9 and 3.

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.