Journal of Biomolecular Structure & Dynamics最新文献

In our preliminary in vitro studies, the Enhydra fluctuans extract demonstrated inhibition of calcium phosphate (brushite) crystals. Human serum albumin (HSA) is known to act as a promoter of brushite crystal growth. Therefore, the present study aims to explore the molecular mechanisms involved in brushite crystal nephrolithiasis by conducting molecular docking of phytoconstituents from E. fluctuans with HSA. Molecular docking is conducted on 35 phytoconstituents of E. fluctuans against HSA, and the top five compounds are further analyzed using Induced Fit Docking (IFD) and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) methods. Molecular dynamics simulations for 50 ns are performed to assess the stability of the protein-ligand complexes. Additionally, in silico physicochemical; absorption, distribution, metabolism, excretion, and toxicity (ADME/T); and pharmacophore modeling studies are conducted. The binding pocket analysis identifies potential binding sites on HSA, and molecular docking reveals Baicalein-7-o-glucoside as the top-performing compound with a strong binding affinity. IFD and MM-GBSA support the stability of the complex. Molecular dynamics simulations indicate stable interactions over the 50 ns period. In silico ADME/T studies suggest that the top five phytoconstituents exhibit drug-like properties with satisfactory pharmacokinetic profiles. Pharmacophore modeling generates a three-point hypothesis, and its validation indicates suitability for the HSA-Baicalein-7-O-glucoside complex. The findings from the current computational investigations indicate that polyphenolic phytoconstituents of E. fluctuans containing the 5,6-dihydroxy chromone ring, such as Baicalein-7-O-diglucoside, may modulate the activity of HSA (PDB ID: 1E7H), potentially inhibiting the process of crystallization.

The NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome is a well-known and frequently cited regulator of caspase-1 activation. It plays a significant role in several pathophysiological processes and is a major regulator of the innate immune response. A growing amount of scientific evidences for its aberrant activation in various chronic inflammatory diseases attracts a growing interest in the development of new NLRP3 inhibitors. One of the successful strategies used to identify new inhibitors is peptide inhibitors. Compared to small molecule inhibitors, peptide inhibitors show greater selectivity and less toxicity. In this study, we used an in-silico mutagenesis approach to design new peptide inhibitors from reported peptide inhibitor of NLRP3. The sequence of the peptide inhibitor against NLRP3 was searched from the literature and modeled using the online server PEP-FOLD3. The in-silico alanine scanning mutagenesis of the reference peptide revealed that residues, Y23, R28, E6, I26, R20, L19, Q33, K11, L14, and K13 have positive affinity values and are therefore better candidates for substitution to increase binding affinity. By replacing these residues, the affinity of the newly designed peptide inhibitors for the NLRP3 PYD protein was significantly increased. Further, molecular dynamics simulations and binding energy calculations validated the stability and higher binding affinities of the newly designed peptide inhibitors compared to the wild-type peptide inhibitor. Our research revealed that all the suggested peptide inhibitors have higher binding affinities for the NLRP3 protein as compared to the native wild-type peptide inhibitor and could block NLRP3-ASC pyrin-pyrin interaction.

Looking for potential alternatives to conventional antibiofilm agents has become a significant concern in treating drug-resistant Pseudomonas aeruginosa infections. In this study, we have tried to identify a potential natural antibacterial and antibiofilm compound against P. aeruginosa. Iron plays a crucial role in the virulence of P. aeruginosa biofilms. It is required for biofilm formation as well as for the production of the key virulence factors. The acquisition and utilization of iron within biofilms contribute to their resilience and ability to cause chronic infections. The interaction between Bacterioferritin (BfrB) and Ferredoxin (Bfd) in P. aeruginosa plays a crucial role in the mobilization of iron. Bfd facilitates the release of iron stored in BfrB, leading to the transfer of Fe²⁺ into the cytosol for bacterial metabolism. This process is vital for maintaining iron homeostasis and supporting various cellular processes. In our study, we have explored the potential of 27 antibacterial flavonoid compounds as ligands to inhibit the interaction between Bacterioferritin (BfrB) and Ferredoxin (Bfd). Through a series of computational analyses, including docking, MMGBSA, ADME, and MD simulation, we have identified Corylifol C as one of the most effective drug candidates capable of blocking the Bacterioferritin-Ferredoxin interaction. These findings suggest that Corylifol C may be used as a potential inhibitor to disrupt iron mobilization and may serve as a promising natural therapeutic agent. The study includes two reference compounds with known potential to block the Bacterioferritin-Ferredoxin interaction. Further wet-laboratory validation can help in establishing the antibacterial and antibiofilm properties of Corylifol C.

Brain cancer represents a highly aggressive malignant tumor with a challenging prognosis and limited treatment options. Employing advanced analytical methods, including Kinase Enrichment Analysis and Disease-Gene Network integration, the research identifies EGFR as a crucial therapeutic target for brain cancer. EGFR, a key player in cellular functions and elevated in various cancers, particularly brain cancer, is targeted using small molecule inhibitors like erlotinib and gefitinib. Despite promising results, challenges such as drug resistance and adverse effects necessitate exploration of alternative therapies. Natural compounds show significant potential for cancer with minimal associated toxicity. Thus, the natural compounds database was explored for EGFR kinase inhibitors. Utilizing molecular docking and dynamic simulation, our study identified five natural compounds-citicoline, silodosin, picroside I, canertinib, and tauroursodeoxycholic acid-as potential EGFR kinase inhibitors. Detailed exploration of their binding attributes, including pose, interacting residues, molecular interactions, dynamic behavior, and predicted binding energy, along with comparisons to the native inhibitor, underscored their potential. Notably, among the five natural compounds screened, canertinib is a known covalent inhibitor of EGFR kinase. However, its specific binding pose remains unexplored. Thus, to uncover the precise binding orientation, covalent docking simulation for canertinib was conducted. Additionally, it is noteworthy that all the five proposed compounds predicted to penetrate the blood-brain barrier, meeting the essential criteria for reaching brain. We anticipate that this study will provide valuable leads for experimental testing in the laboratory, advancing the prospects of brain cancer management.

Acinetobacter baumannii stands out as a potent pathogenic microbe responsible for healthcare-associated infections characterized by elevated morbidity and mortality. This bacterium has acquired a range of mechanisms for resisting antibiotics, resulting in the emergence of strains that can withstand antibiotics from multiple classes. Effectively addressing this urgent concern requires finding ways to overcome these resistance mechanisms. In this context, our study focuses on TetR Transcriptional Factor Regulators (TetR-FTRs). It coordinates functions of tetracycline efflux pump proteins (TetA and TetR) and exert influence over metabolic pathways, quorum sensing, and biofilm formation. The primary objective is to identify potent inhibitors targeting TetR-FTRs through scaffold-based shape screening across thirteen distinct databases. A wide array of in silico techniques was employed, including molecular docking, molecular dynamics simulations, Swiss Similarity search, Virtual Screening, MM/GBSA analysis, ADMET assessment, PAINS assay, SIFT analysis, and MM/PBSA calculations. The initial Swiss similarity search yielded 2178 compounds for subsequent virtual screening, with the application of PAINS analysis rigorously pruning the list, eliminating 14 false positive hits. Further refinement through SIFT approach discriminated closely related interacting compounds into three distinct clusters - ChemBridge5963254, BDH33906706, and ZINC000013607604, which fulfilled all SIFT criteria. Comparative evaluation against reference compounds revealed favorable glide scores, lower binding free energies, and interactions with crucial active site residue Hsd128-Mg²⁺. Molecular dynamics simulations consistently exhibited stable binding for these clusters in contrast to reference compounds. Our analysis underscores three specific compounds, namely ChemBridge5963254, BDH33906706, and ZINC000013607604, as promising candidates for addressing tetracycline resistance and combating A. baumannii infections.

Flavin adenine nucleotide (FAD)-dependent oxidoreductase enzyme Alcohol oxidase (AOX) facilitates the growth of methylotrophic yeast C. boidinii by catabolizing methanol, producing formaldehyde and hydrogen peroxide. Vacuolar Protease-A (PrA) from C. boidinii is responsible for the proteolytic activity of AOX. However, no experimental structures for these enzymes have been reported. This in-silico study involves modeling and interaction analysis of AOX and PrA. A protein-protein interaction study shows that Thr75, Gly74, Arg72, Tyr73, and Met289 amino acids of PrA have shown interaction with AOX. These residues may be crucial for AOX proteolysis. An in-silico study predicts that serine protease inhibitors bind to specific amino acids, potentially obstructing PrA's degradable activity on AOX. PrA does not interact with the FAD binding sites in AOX. Instead, it interacts with AOX at sites (Ser337, Ala34, and Tyr343) where AOX monomers interact, hindering octamer formation the active form of AOX. During simulation, strong dynamics in PrA were found in the loop regions of the structure, as observed in the complexes. This in-silico work aims to corroborate the experimental research, which lacks structural studies on the proteolysis process.

Proteins are essential bimolecular substances that play a crucial role in the maintaining life and are closely associated with its the origin, evolution, and metabolism. Through the use of molecular docking, synchronous fluorescence spectroscopy, ultraviolet-visible absorption, fluorescence, and Fourier transform infrared (FT-IR) spectroscopy, this study sought to clarify the relationship between bovine hemoglobin (BHb) and riboflavin sodium phosphate (RSP) at the normal biological condition. The fluorescence quenching experiment indicated that RSP can cause a static quenching mechanism that quenches BHb's natural fluorescence. Thermodynamic measurements demonstrated that the hydrogen bonding molecular force and hydrophobic contacts caused negative enthalpy and entropy changes during RSP binding to BHb. Using Förster resonance energy transfer, the binding distance between RSP and the BHb tryptophan residues was determined to be 3.11 nm. Fourier transform infrared spectroscopy, synchronous fluorescence, and UV-visible studies revealed that the secondary structure of BHb was considerably altered due to interaction with RSP. The molecular docking simulation revealed that, in addition to hydrophobic interactions, the hydrogen bonds were involved in the interaction of BHb-RSP complex. This study aims to enhance our understanding of the molecular interactions between BHb and RSP, which is significant for elucidating the biochemical pathways involved in metabolic processes.

Plasma Alpha-1-glycoprotein (AGP) binds diverse drugs, its isoforms and their levels vary significantly in acute phases of health. Relative binding pattern of drugs to AGP and albumin has been used to model their release profiles, and structural insights on glycosylated form of AGP will improve predictions. Main challenge is the heavy and heterogeneous glycosylation of AGP molecules. Our small angle X-ray scattering (SAXS) data on plasma extracted AGP showed interparticulate effect from 283 to 313 K which disappeared irreversibly upon further heating to 343K. Using ALPHAFOLD2 server, the protein only portion could be modelled but as expected its theoretical SAXS profile did not match acquired experimental data. Using mass spectra-based information, we attached representative glycan motifs at known sites to compute four models of fully glycosylated AGP. Importantly, calculated SAXS profiles of these models agreed with our experimental data. These representative glycosylated models were further analyzed for molecular motions using Normal Mode Analysis and all-atom Molecular Dynamics simulations in reference to SAXS data. Overall, we show that SAXS data-based models of glycoprotein are better representation of this biopharmaceutical molecule and provide them for structure-based drug profile estimations.

Human P-glycoprotein (hP-gp) is an ATP-binding cassette (ABC) exporter that actively extrudes a wide range of xenobiotics from the cell, thus limiting drug delivery and contributing to multidrug resistance (MDR) in cancers. Recent structural studies have provided insights into how hP-gp binds diverse compounds, but how they are translocated through the membrane remains poorly understood at the atomic level. In this work, we used steered molecular dynamics (SMD) simulations to investigate the molecular mechanism of how hP-gp expels structurally different compounds and which molecular features favor this efflux step. The potential of mean force (PMF) and structural dynamics analysis showed that the bending of TM1 favored the translocation of vincristine, whereas the high flexibility of tariquidar made it easier to pass through the narrow exit tunnel, suggesting a wide opening of the extracellular gate is not required for the efflux of both compounds. Moreover, an alternating-site hydrolysis mechanism may be shared in which ATP bound in the second nucleotide-binding site was preferentially hydrolyzed to provide chemical energy for the flexible-to-rigid transition of TM10. A conserved salt bridge between the fourth intracellular loop and the flexible X-loop was formed in response to ATP binding, which may participate in the interdomain communication. Furthermore, the SMD trajectories revealed two translocation pathways in the hP-gp cavity, one of which is preferentially but non-exclusively taken by a set of compounds. These findings provide deep insights into the efflux mechanism of hP-gp and will help rational design and development of more selective and effective inhibitors.

Haemonchus contortus is a small ruminant gastrointestinal parasitic nematode that rapidly develops resistance to many anthelmintic classes, such as benzimidazoles (eg albendazole). Benzimidazoles are microtubule inhibitors that disrupt the dynamic balance between microtubules and free heterodimeric tubulin. To uncover the molecular mechanism underlying the inhibition of H. contortus microtubule polymerization by benzimidazoles and the resistance caused by polymorphisms, we generated structural models of H. contortus tubulin (TBA-1/TBB-1) wild-type (WT), F167Y, E198A and F200Y variants for in silico modeling in the presence of albendazole. Modeled tubulin dimers were post-analyzed using MM/GBSA, resulting in similar ΔG_bind negative values, suggesting that albendazole binds to the β-tubulin subunit despite polymorphisms. The analysis also revealed secondary structure changes at β-sheet 4 (S4), S6, S8, S9, α-helix 7 (H7) and H8 of the β-tubulin model when albendazole was bound. These changes restrict the movement of the intradimer interface of the α-/β-tubulin heterodimer. We hypothesize that albendazole inhibits the transition of the curved to the straight heterodimer conformation. The microtubule ends shrink by the inhibition of the transition. Also, albendazole connects β4S and β6S in WT+ albendazole, resulting in compaction. Furthermore, we identified a hydrogen bond in F167Y (β: Y167:HH - β: E198:OE1) and F200Y (Y200:HN - β: T199:OG1) variants of the tubulin dimer. These hydrogen bonds could reduce the negative partial charge of E198, which is critical for interacting with albendazole. We postulate that charge modulation or an amino acid change of E198 prevent its interaction with albendazole, leading to resistance.