Journal of Biomolecular Structure & Dynamics最新文献

Alzheimer's disease, marked by memory loss and cognitive decline, is associated with amyloid-beta (Aβ) peptide accumulation in the brain. The enzyme neprilysin (NEP), crucial for Aβ degradation, decreases with age and in sporadic Alzheimer's disease, leading to increased Aβ build-up. This study hypothesized the targeting of enzyme HDAC6, believed to influence NEP activity. An in-silico study was conducted using an FDA-approved drug database, with the focus on their interaction with the HDAC6 structure. Among tested ligands, Panobinostat showed the most favourable interaction with HDAC6. In-vitro experiments on the SH-SY5Y neuronal cell line confirmed these findings, with Panobinostat inhibiting HDAC6, enhancing NEP levels, and reducing Aβ load. The study suggests Panobinostat as a potential Alzheimer's therapeutic agent, mitigating Aβ accumulation via NEP upregulation. Further research is required for comprehensive understanding and validation.Communicated by Ramaswamy H. Sarma.

ORF3a is a conserved accessory protein of SARS-CoV-2, linked to viral infection and pathogenesis, with acquired mutations at various locations. Previous studies have shown that the occurrence of the Q57H mutation is higher in comparison to other positions in ORF3a. This mutation is known to induce conformational changes, yet the extent of structural alteration and its role in the viral adaptation process remain unknown. Here we performed molecular dynamics (MD) simulations of wt-ORF3a, Q57H, and Q57A mutants to analyze structural changes caused by mutations compared to the native protein. The MD analysis revealed that Q57H and Q57A mutants show significant structural changes in the dimer conformation than the wt-ORF3a. This dimer conformer narrows down the ion channel cavity, which reduces Na + or K + permeability leading to decrease the antigenic response that can help the virus to escape the host immune system. Non-bonding interaction analysis shows the Q57H mutant has more interacting residues, resulting in more stability within dimer conformation than the wt-ORF3a and Q57A. Moreover, both mutant dimers (Q57H and Q57A) form a novel salt-bridge interaction at the same position between A:Asp142 and B:Lys61, whereas such an interaction is absent in the wt-ORF3a dimer. We have also noticed that the TM3 domain's flexibility in Q57H is increased because of strong inter-domain interactions of TM1 and TM2 within the dimer conformation. These unusual interactions and flexibility of Q57H mutant can have significant impacts on the SARS-CoV-2 adaptations, virulence, transmission, and immune system evasion. Our findings are consistent with the previous experimental data and provided details information on the structural perturbation in ORF3a caused by mutations, which can help better understand the structural change at the molecular level as well as the reason for the high virulence properties of this variant.Communicated by Ramaswamy H. Sarma.

Almost 80% of lung cancer diagnoses each year correspond to non-small cell lung cancer (NSCLC). The percentage of NSCLC with EGFR overexpression ranges from 40% to 89%, with squamous tumors showing the greatest rates (89%) and adenocarcinomas showing the lowest rates (41%). Therefore, in NSCLC therapy, blocking the EGFR-driven pathway by inhibiting the intracellular tyrosine kinase domain of EGFR has exhibited significant improvement. In this view, several small molecules particularly pyrimidine/fused pyrimidine scaffolds were intended for molecular hybridization to develop EGFR-TK inhibitors. However, the associated limitation such as resistance and genetic mutation along with adverse effects, constrained the long-term treatment and effectiveness of such medication. Therefore, in recent years, pyrimidine derivatives were uncovered as potential EGFR TKIs. The present review summarised the research progress of EGFR TKIs to dazed structure-activity relationship, biological evaluation, and comparative docking studies of pyrimidine compounds. We have added the comparative docking analysis followed by the molecular simulation study against the four different PDBs of EGFR to strengthen the already existing research. Docking analysis unfolded that compound 14 resulted as noticeable with all different PDB and managed to interact with some of the crucial amino acid residues. From a future perspective, researchers must develop a more selective inhibitor, that can selectively target the mutation. Our review will support medicinal chemists in the direction of the development of novel pyrimidine-based EGFR TKIs.Communicated by Ramaswamy H. Sarma.

Uncontrolled cell proliferation is a common definition of cancer. After lung carcinoma, breast neoplasm is the second-most prevalent kind of cancer. The majority of breast cancer cells and healthy breast cells both have receptors for circulating oestrogen and progesterone. In order to promote the development and division of cancer cells, oestrogen and progesterone bind to the receptors and may collaborate with growth factors (such as oncogenes and mutant tumour suppressor genes). As per the literature, Tecteria coadunata (Wall.) C. Chr. has anticancer, antioxidant and anti-inflammatory potential. After the hydroalcoholic extraction of this rhizome, total of 200 phytochemicals were retrieved from HR-LCMS analysis. In this current study, Network pharmacology was carried out to explore the rationale of Tecteria coadunata (Wall.) C. Chr. by using different database using Cytoscape software. The network depicted the interaction of Bioactives with their targets and their association with several disease, especially breast cancer. Tecteria coadunata (Wall.) C. Chr. has offered new relationship with variety of genes and its applications in different types of breast cancers. Further Gene Ontology was carried out and it showed key targets were TP53, BRCA2, PGR and CHEK 2. Further Signalling pathways were also enriched. Flex-X software was used for molecular docking studies, and it verified that Dopaxanthin, Dantrolene and Orotidin shows the highest binding affinities with key targets. Additionally, Pharmacokinetic analysis revealed that all top three lead compounds which follows the Lipinski Rule (Rule of three) without interrupting the conditions of bioavailability with minimal toxicity.Communicated by Ramaswamy H. Sarma.

Human adenovirus (HADV) infection can pose a serious threat to children, leading to a variety of respiratory illnesses and other complications. Particularly, children with weak immune systems are vulnerable to severe adenovirus infections with high mortality. The main focus of this study is to propose new antiviral agents as lead HADV inhibitors for children. So, several antiviral agents used in children were subjected to finding new HADV inhibitors using important computational methods of molecular docking, molecular dynamics (MD) simulation, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculations, density functional theory (DFT), and pharmacokinetic analysis. Molecular docking of standard cidofovir along with other ligands, suggested that sofosbuvir has the highest binding energy (-10.8 kcal/mol), followed by baloxavir marboxil (-10.36 kcal/mol). Further, the analysis of molecular interactions using MD simulation (100 ns) and MM-PBSA indicated that baloxavir marboxil has formed the most stable protein-ligand complex with HADV, followed by sofosbuvir. The binding free energies of baloxavir marboxil and sofosbuvir were found to be -61.724 kJ/mol and -48.123 kJ/mol, respectively. The DFT and drug-likeness properties of these compounds were also investigated. Overall, two antiviral agents, such as baloxavir marboxil, and sofosbuvir are suggested as lead repurposed candidates against HADV.Communicated by Ramaswamy H. Sarma.

To create some novel anticancer molecules, a library of novel series of various triazoles linked to the hydroxyl group of 5,6,7,8-tetrafluoronaphthalen-1-ol (3) was designed and synthesized via CuAAC reaction 'Click Chemistry' of tetrafluoronaphthalene based terminal alkyne with substituted organic azides. The structural characterizations of the targeted Click products 9-18 were confirmed by FTIR, ¹H NMR, ¹⁹F NMR, ¹³C NMR and HRMS spectroscopy. Synthesized compounds were tested in two triple negative breast cancer (TNBC) cell lines to understand their anticancer potentials. According to our findings, compounds 14 and 13 showed high cytotoxicity in BT549 cells at 20 μM and 30 μM, respectively. Moreover, these compounds blocked the migration of BT549 cells. In the MDA-MB-231 cell line, compound 18 exhibited high cytotoxicity and can block cell migration for 24 h. Molecular docking study with synthesized novel compounds was performed by Glide/SP method against SphK1 drug target. Furthermore, molecular dynamics (MD) simulation was carried out for the compounds 12-14 and 18. The compounds 13 and 14 may be potential inhibitor candidates in place of a reference inhibitor. A pharmacophore model was generated with the most potent compound 14, and the approved drugs were screened using the modules of Discovery Studio to find similar drugs. Consequently, this comprehensive study encompassing design, synthesis, in vitro and in silico analyses were correlated with the structure-activity relationship between compounds. The findings have the potential to unveil promising drug candidates for future studies.Communicated by Ramaswamy H. Sarma.

The present study aimed to strategically design a Molecularly Imprinted Polymer (MIP) with selective extraction capabilities for volatile compounds found in pork. These specific volatile compounds, such as 3-methyl-1-butanol, 1-nonanal, octanal, hexanal, 2-pentyl-furan, 1-penten-3-one, N-morpholinomethyl-isopropyl-sulfide, methyl butyrate, and (E,E)-2,4-decadienal, are primarily responsible for the distinctive aroma and flavor characteristics associated with pork. Molecular dynamics simulations were employed to investigate the stability of the pre-polymerization system, simulating the interactions between the volatile compounds as templates, 4-hydroxyethyl methacrylate (HEMA) as monomers, and ethylene glycol dimethacrylate (EGDMA) as crosslinkers. Computational simulations revealed that the optimal mole ratio of 1:4:20 for templates, monomers, and crosslinkers resulted in the most favorable functional radial distribution and exhibited the strongest interactions. To validate the computational findings, additional analyses were performed utilizing Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA), radial distribution function (RDF), and hydrogen bond (HBond) occupancy. The calculated binding free energy demonstrated that all template molecules were capable to bind with both the monomers and crosslinkers, including 1-penten-3-one and N-morpholinomethyl-isopropyl-sulfide displaying the strongest interactions, with values of -12,674 kJ/mol and -11,646 kJ/mol, respectively. The congruence between the results obtained from the molecular simulation analyses highlights the crucial role of molecular dynamics simulations in the study and development of MIP for the analysis of marker compounds present in pork.Communicated by Ramaswamy H. Sarma.

Protein-protein and protein-peptide interactions (PPI and PPepI) belong to a similar category of interactions, yet seemingly subtle differences exist among them. To characterize differences between protein-protein (PP) and protein-peptide (PPep) interactions, we have focussed on two important classes of residues-hotspot and anchor residues. Using implicit solvation-based free energy calculations, a very large-scale alanine scanning has been performed on benchmark datasets, consisting of over 5700 interface residues. The differences in the two categories are more pronounced, if the data were divided into three distinct types, namely - weak hotspots (having binding free energy loss upon Ala mutation, ΔΔG, ∼2-10 kcal/mol), moderate hotspots (ΔΔG, ∼10-20 kcal/mol) and strong hotspots (ΔΔG ≥ ∼20 kcal/mol). The analysis suggests that for PPI, weak hotspots are predominantly populated by polar and hydrophobic residues. The distribution shifts towards charged and polar residues for moderate hotspot and charged residues (principally Arg) are overwhelmingly present in the strong hotspot. On the other hand, in the PPepI dataset, the distribution shifts from predominantly hydrophobic and polar (in the weak type) to almost similar preference for polar, hydrophobic and charged residues (in moderate type) and finally the charged residue (Arg) and Trp are mostly occupied in the strong type. The preferred anchor residues in both categories are Arg, Tyr and Leu, possessing bulky side chain and which also strike a delicate balance between side chain flexibility and rigidity. The present knowledge should aid in effective design of biologics, by augmentation or disruption of PPIs with peptides or peptidomimetics.Communicated by Ramaswamy H. Sarma.

Ribosome Inactivating Proteins (RIPs) act by irreversibly depurinating the 28S rRNA ricin-sarcin loop (SRL) of the eukaryotic ribosome resulting in protein synthesis inhibition. In general, they consist of two variants: Type I which is single chained (∼30 kDa), and Type II, a more toxic variant which is a Type I N-glycosidase chain covalently linked to a lectin chain. These proteins are believed to play a pivotal role in defence mechanisms. Intriguingly, non-toxic variants of such toxic proteins do exist in nature. To explore their mode of action, in the present study we have selected three toxic (Ricin, Ebulin and HmRIP) as well as two non-toxic (BGSL and SGSL) RIPs and performed molecular docking and molecular dynamic simulations with the SRL loop. This study throws light on the structural stability and plasticity of the toxic and non-toxic RIP complexes. Furthermore, analysis of the active site cavity volume and binding free energy calculations reveal that the SRL, particularly the specific adenine (A4605), is relatively unstable in the case of non-toxic RIPs which is also supported by the free binding energy calculations, and the pocket size analysis indicates the abnormal increase in active site cavity volume of non-toxic RIPs with time. This first-of-its-kind comprehensive study of toxic and non-toxic RIPs gives insights about the mode of action and the dynamic nature of their interaction with the SRL loop. These observations will be helpful in the development of toxoids against RIPs and also in designing novel therapeutic approaches against human diseases.

Satureja nabateorum, known as Nabatean savory is a Lamiaceae plant native to the Arabian Peninsula, specifically in the mountainous regions of Saudi Arabia. The study aims to investigate the phytochemical components of the S. nabateorum leaves (SNL) and stems (SNS) extract and to assess their antioxidant, antimicrobial, and antiproliferative properties. Methanol extracts from leaves and stems were analyzed for chemical constituents using the GC-MS technique. Antioxidant capacities were measured using hydrogen peroxide and ABTS radical-scavenging methods, and antimicrobial activity was tested against various microorganisms. Cytotoxic activity on four human malignant cell lines was assessed using MTT and flow cytometry. Molecular docking and molecular dynamics studies were conducted to understand the interactions and binding modes of the extracted compounds at a molecular level. GC-MS analysis of SNL extract revealed thymol, carvacrol, and p-cymen-8-ol as major constituents. SNS extract contained β-sitosterol, stigmasterol, lupeol, and lup-20(29)-ene-3β,28-diol. SNS extract exhibited more potent antioxidant, antimicrobial, and anticancer effects than SNL extract. The extract, SNS, exhibited potential toxicity in A549 cells with an IC₅₀ value of 3.62 µg/mL and induced marked apoptotic effects with S phase-cell cycle arrest. SNS extract also showed higher levels of Caspase 3, Bax, p53, and the Bax/Bcl2 ratio and lower levels of Bcl-2. Molecular docking and dynamic simulation supported these findings, targeting the EGFR TK domain. The study suggests that the S. nabateorum stem extract holds promise as a potent antimicrobial, antioxidant, and anticancer agent. It provides valuable insights for considering the extract as a substitute for chemotherapy and/or protective agents.