Journal of Biomolecular Structure & Dynamics最新文献

Non-small-cell lung cancer (NSCLC) is one of the most deadly tumors characterized by poor survival rates. Advances in therapeutics and precise identification of biomarkers can potentially reduce the mortality rate. Thus, this study aimed to identify a set of common and stable gene biomarkers through integrated bioinformatics approaches that might be effective for NSCLC early diagnosis, prognosis, and therapies. Four gene expression profiles (GSE19804, GSE19188, GSE10072, and GSE32863) downloaded from the Gene Expression Omnibus database to identify common differential expressed genes (DEGs). A total of 213 overlapping DEGs (oDEGs) between NSCLC and healthy samples were identified by using statistical LIMMA method. Then 6 common top-ranked key genes (KGs) (CENPF, CAV1, ASPM, CCNB2, PRC1, and KIAA0101) were selected by using four network-measurer methods in the protein- protein interaction network. The GO functional and KEGG pathway enrichment analysis were performed to reveal some significant functions and pathways associated with NSCLC progression. Transcriptional and post-transcriptional factors of KGs were identified through the regulatory interaction network. The prognostic power and expression level of KGs were validated by using the independent data through the Kaplan-Meier and Box plots, respectively. Finally, 4 KGs-guided repositioning candidate drugs (ZSTK474, GSK2126458, Masitinib, and Trametinib) were proposed. The stability of three top-ranked drug-target interactions (CAV1 vs. ZSTK474, CAV1 vs. GSK2126458, and ASPM vs. Trametinib) were investigated by computing their binding free energies for 140 ns MD-simulation based on MM-PBSA approach. Therefore, the findings of this computational study may be useful for early prognosis, diagnosis and therapies of NSCLC.

Metabolic reprogramming is one of the hallmarks of breast cancer (BC), involving elevated synthesis and uptake of lipids, for catering to increased energy demand of cancer cells and to suppress the host immune system. Besides promoting proliferation and survival of BC cells, lipid metabolism reprogramming (LMR) is associated with stemness and chemoresistance. Recently, lignans have been reported for their therapeutic potential against different cancers, including BC. Here, we explored the potential of lignans to target LMR pathways in BC through computational approach. Initially, 88 lignans having potential anticancer activities, underwent druglikeness and pharmacokinetics analysis, displaying promising pharmacokinetic properties, except for 13 molecules with violations. Molecular docking assessed the interaction of 88 lignans (NPACT) with therapeutic targets of LMR including 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), Sterol regulatory element-binding proteins 1 and 2 (SREBP1 and 2), Low-density lipoprotein receptor (LDLR), Acetyl-CoA Acetyltransferase 1 (ACAT1), ATP-binding cassette transporter (ABCA1), Liver X receptor α (LXRα), Apolipoprotein A1 (APOA1), Fatty Acid Synthase (FASN), Peroxisome proliferator-activated receptor gamma (PPARG), Stearoyl-CoA desaturase (SCD1), Acetyl-CoA carboxylase 1 and 2 (ACC1/ACACA, and ACC2/ACACB). In silico screening revealed sesamin (SE) as the best-identified hit that showed stable and consistent binding with all the selected targets of LMR. The stability of these complexes was validated by a 100 ns simulation run, and their binding free energy calculation was determined by MM-PBSA method. Interestingly, SE modulated the mRNA expression of genes involved in LMR in BC cell lines, MCF-7 and MDA-MB-231, thereby suggesting its potential as an inhibitor of LMR.

From the most prevalent cancers, breast and lung cancers have a meager survival rate for both men and women. These two cancers are related to each other. Breast cancer can possibly spread to the lungs or the region between the lung and the chest wall. The organic heterocyclic compounds are expected to possess some anti-cancerous properties. Hence, this study is to investigate the molecular characteristics of the derivatives of alkyl-5-hydroxy-7-aryl-5-methyl-1,3-dioxo-2-phenyl hexahydropyrazolo[1,2a] (Asif, 2017; Hei et al., 1996; Kumar et al., 2013) triazole-6-carboxylate and the drugability of these compounds have also been examined against estrogen receptor (ER) mutant L536S, which causes ER-positive breast cancer, and anaplastic lymphoma kinase responsible for non-small cell lung cancer (NSCLC). DFT and TDDFT have been used to study all the derivatives with B3LYP/6-311++G(d, p) basis set. Substituent effects via ¹H NMR,¹³C NMR, IR, UV and HOMO-LUMO energy gaps of -CH₃, -F, -Cl, -Br, -I, -NO₂, and -SO₃H groups at the para positions of 7-aryl substituent present in triazole compound have been studied. The global reactivity of these compounds is also being discussed in terms of band gap (E_HOMO-E_LUMO). The NTO analysis monitors and characterizes the direction and nature of charge transfer. The drug-likeness using Lipinski's Rule of Five, followed by molecular docking of the compounds with the target proteins have also been studied. Molecular dynamics simulations and free energy calculations were conducted for all protein-ligand complexes to predict potential inhibitors targeting the proteins.

The main objective of this study is to produce novel triazoles-loaded tetrazoles, which are crucial in the development of prospective therapeutic agents in medicinal chemistry. Recent investigations have found a wide range of uses for these derivatives, and they are prospective lead molecules for the synthesis of substances with enormous therapeutic utility for various diseases, especially for bacterial therapy. New series of 1,2,3-triazole derivatives have been synthesized from methyl (2S,4S)-4-azido-1-(2,4-difluoro-3-methylbenzoyl)pyrrolidine-2-carboxylate (5) using a well-established click reaction that has several advantages to afford a novel heterocyclic compound based on tetrazole moieties. The structures of the new compounds were ascertained by spectral means (IR, NMR: ¹H and ¹³C) and mass spectrum. All the synthesized compounds were assessed in vitro antimicrobial activity against Gram-+ve (S. pyogenes, S. aureus and B. subtilis), Gram-negative (E. coli and P. aeruginosa) bacterial and fungal strains A. flavus and C. albicans. The prepared compounds 7b and7f proved to have strong impact on S. aureus and S. pyogenes strains with MICs of 2.5 µg/mL and 1.5 µg/mL respectively. Among the tested compounds, hybrids 7b, 7f, 7h, and 7i exhibited exceptional antifungal susceptibilities against C. albicans with zone of inhibition 25 ± 0.2, 30 ± 0.3, 30 ± 0.1, and 28 ± 0.2 mm respectively, which is stronger than fluconazole (28 ± 0.1 mm). The capacity of ligand 7f to form a stable compound on the active site of S. aureus complex with DNA Gyrase (2XCT) was confirmed by docking studies using amino acids Ala233(A), Arg234(A), Gly283(A), Ser286(A), Lys52(A), His280(A), Gly51(A), His282(A) and Val246(A). Furthermore, the physicochemical and ADME (absorption, distribution, metabolism, and excretion) filtration molecular properties, estimation of toxicity, and bioactivity scores of these scaffolds were evaluated.

Garuga pinnata a tree spotted in the Asian continent constitutes of constellation of phytochemicals in the whole tree from which the alcoholic extract of the leaf is the abundant source. The phytochemicals namely Amentoflavone, Garuganin-1, Garuganin-3, Garuganin-4, and Garuganin-5 were considered for the study as they have the anti-Alzheimer's potential but the biological target has not been reported. So, to identify the target the phytochemicals were scrutinized by employing in silico methodologies namely molecular docking, molecular dynamics simulation, and ADMET prediction. Molecular docking revealed that Amentoflavone occupied the active site of the NMDA, and established interactions with Gln110, Glu236, Ile133, and Asp136 with an excellent docking score of -8.535 kcal/mol. Amentoflavone with the best docking score was selected for molecular dynamics which revealed that Amentoflavone maintained stability in the active site of the NMDA receptor with three hydrogen bond interactions in 100 ns time scale of the trajectory. Amentoflavone demonstrated an encouraging ADMET profile as compared to other phytochemicals. In the nut shell Amentoflavone displayed excellent in silico results and further may demonstrate an excellent in vitro NMDA inhibitory potential.

The SPINK2 protein, encoded by the SPINK2 gene, plays an essential role in the normal development of spermatozoa, and its deficiency is associated with spermatogenesis disorders ranging from aspermia to azoospermia. This study aimed to identify the most deleterious variants of the SPINK2 gene and to evaluate their effects on protein structure and function through an in silico approach. A total of 8,028 variants were identified, including 72 missense variants. Using 11 bioinformatics tools, six variants (P50L, T58I, C66Y, E62A, P42S, and P45L) were predicted to have deleterious effects. Protein-protein interaction analysis using the STRING database revealed strong functional associations between SPINK2, SPINK1, and ACR, and medium-confidence associations with SPINK4, SPINK13, PMPCA, KLK4, SPINK9, SPINK6, SPACA1, and NUDT8. Local structural analysis showed that variants such as T58I and C66Y gained additional hydrophobic interactions, whereas P50L and P42S lost key interactions, potentially impairing protein stability and function. Molecular dynamics simulations using GROMACS revealed that P50L enhances protein stability, reduces amino acid flexibility, and increases the overall dimensions of the protein. T58I had a mild effect on stability, whereas E62A and C66Y decreased stability and flexibility while increasing protein size. P42S and P45L induced slight stability alterations, reduced flexibility, and enlarged the protein. Overall, these structural and dynamic changes suggest functional impairment of SPINK2. To our knowledge, this is the first study to identify six deleterious SPINK2 variants with potential roles in the disruption of spermatogenesis, providing a foundation for future functional and clinical investigations.

This study aimed to induce fibril formation in human insulin under physiological conditions and to investigate the inhibitory potential of caffeic acid (CA) on these fibrils in-vitro. Various techniques including circular dichroism (CD) spectroscopy, Thioflavin T, ANS fluorescence, Rayleigh light scattering (RLS), and turbidity analysis were conducted to elucidate fibril formation and CA inhibition potential. Fibril formation in insulin was induced by heating (37 °C) and agitation (600 rpm) significantly increased (27.01-fold) the ThT binding after 120 h of incubation. Aggregation also increased turbidity and enhanced RLS fluorescence at 350 nm. Secondary structure analysis revealed at loss of α-helical content and a concomitant increase in β-sheet content in human insulin following aggregation. The presence of varying concentrations of CA resulted in fewer perturbations in the secondary structure of insulin compared with the aggregated insulin sample. Fibril formation was also reduced (80%) in the presence of CA (500 µM). To gain insight, the biophysical interactions between CA and insulin were studied. CA showed moderate affinity (5.54 × 10³ M^-1) towards insulin in static quenching mode. The positive ΔH and ΔS values obtained indicate that the reaction was driven by hydrophobic interactions and the negative value of ΔG indicates a spontaneous reaction between the complexes. Docking analysis showed the interaction of CA with various amino acids of insulin via H-bonds, van der Waals forces, and hydrophobic interactions. Molecular simulations of RMSD, RMSF, and R_g showed that CA formed a stable complex with insulin.

A novel PET hydrolase-like enzyme identified from metagenomic databases using HMMR search was computationally fused with five different carbohydrate-binding modules (CBMs). AlphaFold3 predicted the 3D structures of the fused enzyme-CBM, which were validated using ERRAT, Verify3D, and PROCHECK. Molecular docking was performed with polycaprolactone triol using AutoDock Vina, followed by 100 ns molecular dynamics (MD) simulations using AMBER. Trajectory analyses and binding free energy calculations (QM/MM-GBSA) were conducted. The putative PET hydrolase-like enzyme shared 49.62% similarity with Ideonella sakaiensis PETase (5XJH). The fused models exhibited the best stability, with an instability index of <40 and a thermostability aliphatic index between 58.83 and 68.27. Structure validation confirmed high-quality 3D models, with >90% of the residues in the allowed Ramachandran regions. All the fused models showed favourable binding to PCL-triol, exhibiting strong interactions. In MD simulations, BlCBM5 and TrCBM complexes displayed a minimal fluctuation: all-atom RMSD ∼0.35 and ∼0.45 nm, backbone RMSD ∼0.48, ∼0.41 nm, atom contacts ∼4.2-5, ∼2-6, and H-bonds ∼2-5, ∼1-2, respectively. The BlCBM5 and TrCBM complexes showed the lowest binding energies, with MM-GBSA values of -36.66 ± 0.12 and -21.48 ± 0.11 kcal/mol, and QM/MM-GBSA values of -37.36 ± 0.13 and -21.70 ± 0.11 kcal/mol, respectively. Residue-level analysis identified key contributors (M133, W157, and F62) in both models. BlCBM5 and TrCBM complexes were the top candidates for enhancing PCL plastic degradation. The findings of this study were based on predictive insights, and experimental validation is required in the future.

Microtubule affinity-regulating kinase 4 (MARK4) is a viable therapeutic target for neurodegenerative disorders and various solid cancers. To identify small molecule inhibitors targeting MARK4, a virtual high-throughput screening of a kinase-specific library and an in-house library was performed using Schrödinger Maestro suite. The study identified JMI-1094 (Docking score -8.486 kcal/mol) as a promising compound among top ten hits with high binding affinities for MARK4, exhibiting strong interactions with active site residues Lys85, Glu133, and Ala135. The binding potential is also supported by Prime/MM-GBSA binding free energy calculations. The stability of MARK4-JMI-1094 complex was also accessed through MD simulation studies of 100 ns. The analysis of MD trajectories in terms of root mean square deviation (RMSD) and root mean square fluctuation (RMSF) revealed that MARK4-JMI-1094 complex displayed lower RMSD values than the apoprotein, signifying a strong and stable binding of JMI-1094 with MARK4. Hydrogen bond interactions with Glu133 and Ala135 persisted for 99% of the simulation time. The cell-based tau-phosphorylation assay suggests that it substantially inhibits the activity of MARK4. Moreover, the efficacy of JMI-1094 was evaluated high MARK4 expressing cell lines from breast (MCF-7) and non-small cell lung cancer (A549) and it decreased the viability of these cell lines with an IC₅₀ value of 4.14 µM and 6.22 µM, respectively. The treatment with JMI-1094 significantly decreased the colonization and cell migration potential of MCF-7 and A549 cell lines, and induced apoptosis. These findings suggest JMI-1094 as a promising MARK4 inhibitor with potential future therapeutic implications in MARK4-mediated cancer(s).

The structural and functional consequences of mutations located throughout the S1 and S2 subunit domains of spike protein among omicron and D614G-mutant originating forms of the SARS-CoV-2 virus are examined. These structural mutations were identified by a mass-based phylogenetics approach. The T95I mutation, located in the S1 N-terminal domain, and the T547K mutation of the receptor-binding domain both help to stabilise the spike protein structure and contribute to viral fitness in omicron variants. The D796Y within the N-terminal portion of the S2 subunit, also stabilises the protein, while the effects of Q954H and N969K combine to reduce infectivity through displacement of the backbone of the heptad repeat 2 (HR2) region. The N856K mutation, within the fusion peptide region, introduces a stabilising H-bond at residue T572 that both alters the S1/S2 interaction and hampers conformational change resulting in a mixed stabilisation effect.