Journal of Biomolecular Structure & Dynamics最新文献

Protein structure prediction (PSP) is a key concern in computational biology, which is considered a challenging task that is vital to determine the structure and the protein function since each protein possesses a definite shape, whereas the protein secondary structure prediction (PSSP) is the foundation for three-dimensional PSP. An Advanced hybrid ensemble deep predictor is utilized for predicting the structure of a protein using Long-Short Term Memory (LSTM), in which the performance of the predictor is improved for obtaining the features through the Salp-J Colony Optimization, which is developed by integrating the features of three optimizations the exploration behavior of Ulmaris, the immune system of virus colony and the teamwork of salp for solution update that helps to predict the accurate protein structure. The proposed method achieved the value of 99.1% accuracy, 99.5% sensitivity, 98.85% specificity, and 0.9% error at the 80% of training percentage 90 using CullPDB. Similarly, in Protein Net, the attained value of accuracy is 97.27%, sensitivity is 98.13%, specificity is 97%, and error is 2.7% concerning training percentage 90%.

Fanconi anemia (FA) is a genetic disorder that occurs when certain genes responsible for repairing DNA replication and promoting homologous recombination fail to function properly. This leads to severe clinical symptoms and a wide range of cancer-related characteristics. Recent treatment approaches for FA involve hematopoietic stem cell transplantation (HSCT), which helps restore the population of stem cells. A survival study using p-values indicated that specific hub genes play a significant role in diagnosing and predicting the disease. To find potential medications that interact with the identified hub genes, researchers inferred drugs. Among hub genes, TP53 was found to be particularly promising through computational analysis. Further investigation focused on two drugs, Topiramate and Tocofersolan predicted based on drug bank database analysis. Molecular docking strategies were employed to assess the best binding pose of these drugs with TP53. Topiramate showed a binding affinity of -6.5 kcal/mol, while Tocofersolan showed -8.5 kcal/mol against the active residues within the binding pocket. Molecular dynamics (MD) simulations were conducted to observe the stability of each drug's interaction with the TP53 protein over time. Both drugs exhibited stable confirmation with only slight changes in the loop region of the TP53 protein during the simulation intervals. Results also shows that there was a high fluctuation observed during apo-sate simulation time intervals as compared to complex system. Hence, it is suggested that the exploration of structure-based drug design holds promising results to specific target. This could potentially lead to a breakthrough in future experimental approaches for FA treatment.

Flavonoids are significant dietary components and have ability to coordinate with metal ions to produce novel drug discovery leads that are superior to those of the parent flavonoids. Here, in this report, we have synthesized chrysin-Cu(II) complex (as per reported article) and characterized it further with different analytical techniques. The synthesized complex was evaluated for radical scavenging and cell cytotoxicity studies where it exhibited enhanced activity as compared to bare chrysin. The interaction studies of the complex with ct-DNA (K_b ⁓ 10⁵ M^-1), human serum albumin (HSA) and ovalbumin (K_b ⁓ 10⁴ M^-1) were evaluated using multi-spectroscopic and molecular docking studies. Groove binding mode with ct-DNA was observed as confirmed from competitive displacement studies, viscosity measurement, melting temperature estimation and docking analyses. The complex exhibited comparatively higher affinity towards ct-DNA which indicated it efficient transportation by the carrier proteins and controlled release in the target DNA.

Three new thymol-based molecules were synthesized and evaluated as anticancer, antimicrobial and antioxidant agents. Liver, colon, lung and prostate cancer cell lines were utilized in cytotoxicity tests. The results demonstrated that synthesized molecules had a cytotoxic effect against the screened cell lines. One of the molecules (4a) was found to have a higher efficacy towards the colon cancer cell line (DLD-1) with an IC₅₀ value of 12.39 µM and the other (4c) towards the prostate cancer cell line (PC3) with an IC₅₀ value of 7.67 µM than the positive control drug cisplatin. To assess the antimicrobial activity of molecules (4a-c), Gram-positive bacteria, Gram-negative bacteria and yeast were subjected to agar disc diffusion and broth microdilution assays. The investigation of antioxidant potential was conducted using the DPPH radical scavenging activity assay. While all compounds displayed strong cytotoxic and antioxidant properties, they exhibited only moderate antimicrobial activity. Molecular docking studies were performed on epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR-2), focal adhesion kinase (FAK), B-Raf and phosphoinositide 3-kinase (PI3K). The binding energies and interactions obtained from the docking results of compounds (4a-c) supported the experimental results. Drug similarity rates and pharmacokinetic properties were analyzed with the absorption, distribution, metabolism and excretion (ADME) method. Geometric parameters such as chemical potential (µ), electrophilicity index (ω) and chemical softness (σ) of compounds (4a-c) were calculated using the 6-31*G basis set B3LYP method.

Focal Adhesion Kinase (FAK) is an important target for tumor therapy and is closely related to tumor cell genesis and progression. In this paper, we selected 46 FAK inhibitors with anticancer activity in the pyrrolo pyrimidine backbone to establish 3D/2D-QSAR models to explore the relationship between inhibitory activity and molecular structure. We have established two ideal models, namely, the Topomer CoMFA model ($q^2$= 0.715, $r^2$= 0.984) and the Holographic Quantitative Structure-Activity Relationship (HQSAR) model ($q^2$= 0.707, $r^2$= 0.899). Both models demonstrate excellent external prediction capabilities.Based on the QSAR results, we designed 20 structurally modified novel compounds, which were subjected to molecular docking and molecular dynamics studies, and the results showed that the new compounds formed many robust interactions with residues within the active pocket and could maintain stable binding to the receptor proteins. This study not only provides a powerful screening tool for designing novel FAK inhibitors, but also presents a series of novel FAK inhibitors with high micromolar activity that can be used for further characterization. It provides a reference for addressing the shortcomings of drug metabolism and drug resistance of traditional FAK inhibitors, as well as the development of novel clinically applicable FAK inhibitors.

Cancer and obesity are two important public health problems. This study aimed to investigate the role of genetic variants and haplotypes of miRNA host genes in cancer and obesity. Data from the catalog of genome-wide association studies (GWAS) were used to find significant variants (index). Then, 1000-genome phase 3 data were used to find haplotypic variants (proxy) associated with these diseases. The candidate variants and haplotypes were identified from proxy and index variants. Finally, SNP function analysis was performed. All GWAS-significant cancer-associated miRNA host gene variants, including MIR4713HG, MIR663AHG, MIR99AHG and MIR4435-2HG, were also significantly associated with obesity. The rs703764 variant was common between cutaneous melanoma and obesity traits in the European population (P ≤ 5E-8). The rs2414098 variant was associated with endometrial cancer (P ≤ 5E-13), and the rs7173595 variant was associated with waist-hip ratio (P ≤ 5E-13) and new CGGCATCA haplotypic located at MIR4713HG was identified in the European population. In addition, the ATCTTGTT haplotype for rs17041868 in MIR4435-2HG was identified to be associated with obesity traits (waist-hip ratio and BMI) in the European population (P ≤ 5E-8). This study found that rs703764 is a common genetic marker between cancer and obesity. The CGGCATCA haplotype is common between endometrial cancer and waist-hip ratio. Also, ATCTTGTT haplotype is associated with obesity traits. These results indicate that the variants and haplotypes of miRNAs host genes play an important role between cancer and obesity in the European population. It is suggested to investigate the effect of these structures in other populations.

CD1 immunoreceptors are a non-classical major histocompatibility complex (MHC) that present antigens to T cells to elucidate immune responses against disease. The antigen repertoire of CD1 has been composed primarily of lipids until recently when CD1d-restricted T cells were shown to be activated by non-lipidic small molecules, such as phenyl pentamethyl dihydrobenzofuran sulfonate (PPBF) and related benzofuran sulfonates. To date structural insights into PPBF/CD1d interactions are lacking, so it is unknown whether small molecule and lipid antigens are presented and recognized through similar mechanisms. Furthermore, it is unknown whether CD1d can bind to and present a broader range of small molecule metabolites to T cells, acting out functions analogous to the MHC class I related protein MR1. Here, we perform in silico docking and molecular dynamics simulations to structurally characterize small molecule interactions with CD1d. PPBF was supported to be presented to T cell receptors through the CD1d F' pocket. Virtual screening of CD1d against more than 17,000 small molecules with diverse geometry and chemistry identified several novel scaffolds, including phytosterols, cholesterols, triterpenes, and carbazole alkaloids, that serve as candidate CD1d antigens. Protein-ligand interaction profiling revealed conserved residues in the CD1d F' pocket that similarly anchor small molecules and lipids. Our results suggest that CD1d could have the intrinsic ability to bind and present a broad range of small molecule metabolites to T cells to carry out its function beyond lipid antigen presentation.

Leukemia is a haematological malignancy affecting blood and bone marrow, ranking 10^th among the other common cancers. DNA methylation is an epigenetic dysregulation that plays a critical role in leukemogenesis. DNA methyltransferases (DNMTs) such as DNMT1, DNMT3A and DNMT3B are the key enzymes catalysing DNA methylation. Inhibition of DNMT1 with secondary metabolites from medicinal plants helps reverse DNA methylation. The present study focuses on inhibiting DNMT1 protein (PDB ID: 3PTA) with annonaceous acetogenins through in-silico studies. The docking and molecular dynamic (MD) simulation study was carried out using Schrödinger Maestro and Desmond, respectively. These compounds' drug likeliness, ADMET properties and bioactivity scores were analysed. About 76 different acetogenins were chosen for this study, among which 17 showed the highest binding energy in the range of -8.312 to -10.266 kcal/mol. The compounds with the highest negative binding energy were found to be annohexocin (-10.266 kcal/mol), isoannonacinone (-10.209 kcal/mol) and annonacin (-9.839 kcal/mol). MD simulation results reveal that annonacin remains stable throughout the simulation time of 100 ns and also binds to the catalytic domain of DNMT1 protein. From the above results, it can be concluded that annonacin has the potential to inhibit the DNA methylation process and prevent leukemogenesis.

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.

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.