Journal of Biomolecular Structure & Dynamics最新文献

A cystine-dense peptide (CDP) named TfRB1 was identified for its ability to bind to the transferrin receptor (TfR). CDPs are stabilized by their disulfide bonds, and variants of TfRB1 - specifically TfRB1G1, TfRB1G2, and TfRB1G3 - are explored for their potential to transport molecules across the blood-brain barrier (BBB) into the central nervous system (CNS). This study employed molecular modeling and dynamics simulations to characterize the interactions between these TfRB1 variants and TfR. Binding free energy calculations showed a strong correlation with experimental binding affinities of -10.99 kcal/mol for TfRB1G2 and -13.18 kcal/mol for TfRB1G3, with a relative error of 1.98%. The key forces driving these interactions include electrostatic and van der Waals forces, with mutations in TfRB1G3 (T9M and A13D) enhancing its binding affinity through improved interactions with residues such as Arg633. The free energy landscape analysis revealed that TfRB1G3 maintains the N-terminal residues of TfR in an α-helical conformation, unlike TfRB1G2. Per-residue free energy decomposition identified key residues - Leu619, Arg629, Tyr643, and Phe650 - as crucial for TfR binding, underscoring their competitive nature with transferrin. Additionally, Glu612, which is favorable for binding in TfRB1G2, becomes unfavorable in TfRB1G3. Conversely, Arg633 shifts from unfavorable in TfRB1G2 to favorable in TfRB1G3, compensating for the loss of favorable interaction with Glu612. These findings provide valuable molecular insights into the TfRB1 peptides' potential as drug carriers, highlighting their capability to deliver molecules to the CNS and compete with transferrin for BBB transport.

The spread of drug-resistant strains of tuberculosis has hampered efforts to control the disease worldwide. The Mycobacterium tuberculosis cell wall envelope is dynamic, with complex features that protect it from the host immunological response. As a result, the bacterial cell wall components represent a potential target for drug discovery. Protein-protein interaction networks (PPIN) are critical for understanding disease conditions and identifying precise therapeutic targets. We used a rational theoretical approach by constructing a PPIN with the proteins involved in cell wall biosynthesis. The PPIN was constructed through the STRING database and embB was identified as a key protein by using four topological measures, betweenness, closeness, degree, and eigenvector, in the CytoNCA tool in Cytoscape. The 'Drug repurposing' approach was employed to find suitable inhibitors against embB. We used the Schrödinger suites for molecular docking, molecular dynamics simulation, and binding free energy calculations to validate the binding of protein with the ligand. FDA-approved drugs from the ZINC database and DrugBank were screened against embB (PDB ID: 7BVF) using high-throughput virtual screening, standard precision, and extra precision docking. The drugs were screened based on the XP docking score of the standard drug ethambutol. Accordingly, from the top five hits, azilsartan and dihydroergotamine were selected based on the binding free energy values and were further subjected to Molecular Dynamics Simulation studies for 100 ns. Our study confirms that Azilsartan and Dihydroergotamine form stable complexes with embB and can be used as potential lead molecules based on further in vitro and in vivo experimental validation.Communicated by Ramaswamy H. Sarma.

Apoptosis is a critical process that regulates cell survival and death and plays an essential role in cancer development. The Bcl-2 protein family, including myeloid leukemia 1 (Mcl-1), is a key regulator of the intrinsic apoptosis pathway, and its overexpression in many human cancers has prompted efforts to develop Mcl-1 inhibitors as potential anticancer agents. In this study, we aimed to design new Mcl-1 inhibitors using various computational techniques. First, we used the Mcl-1 receptor-ligand complex to build an e-pharmacophore hypothesis and screened a library of 567,000 fragments from the Enamine database. We obtained 410 fragments and used them to design 92,384 novel compounds, which we then docked into the Mcl-1 binding cavity using HTVS, SP, and XP docking modes of Glide. To assess their suitability as drug candidates, we conducted MM-GBSA calculations and ADME prediction, leading to the identification of 10 compounds with excellent binding affinity and favorable pharmacokinetic properties. To further investigate the interaction strength, we performed molecular dynamics simulations on the top three Mcl-1 receptor-ligand complexes to study their interaction stability. Overall, our findings suggest that these compounds have promising potential as anticancer agents, pending further experimental validation such as Mcl-1 apoptosis Assay. By combining experimental methods with various in silico approaches, these techniques prove to be invaluable for identifying novel drug candidates with distinct therapeutic applications using fragment-based drug design. This methodology has the potential to expedite the drug discovery process while also reducing its costs.Communicated by Ramaswamy H. Sarma.

Studying interactions between drugs and cell membranes is of great interest to designing novel drugs, optimizing drug delivery, and discerning drug mechanism action. In this study, we investigated the physical properties of the bilayer membrane model of POPC upon interaction with ibuprofen (IBU) using molecular dynamics simulations. The area per lipid (APL) was calculated to describe the effect of ibuprofen on the packing properties of the lipid bilayer. The APL was 0.58 nm² and 0.63 nm² for the membrane in low and high IBU respectively, and 0.57 nm² for the membrane without IBU. Our finding showed that the mean square deviation (MSD) increased with increased ibuprofen content. In addition, the order parameter for the hydrocarbon chain of lipids increased with increased ibuprofen content. There was an increment in the transfer free energy after the head group region while it was maximum in the hydrophobic core for hydrogen peroxide (H₂O₂) (∼6.2 kcal.mol^-1) and H₂O (∼3.4 kcal.mol^-1) which then decreased to respective values of (∼4.6 kcal.mol^-1), and (∼2.3 kcal.mol^-1) at the center of the bilayer in the presence of IBU. It seems that in the presence of ibuprofen, the free energy profile of the permeability of water and H₂O₂ significantly decreased. These findings show that ibuprofen significantly influences the physical properties of the bilayer by decreasing the packing and intermolecular interaction in the hydrocarbon chain region and increasing the water permeability of the bilayer. These results may provide insights into the local cytotoxic side effects of ibuprofen and its underlying molecular mechanisms.Communicated by Ramaswamy H. Sarma.

The stability and activity of lipase in organic media are important parameters in determining how quickly biocatalysis proceeds. This study aimed to examine the effects of two commonly used alcohols in industrial applications, methanol (MtOH) and ethanol (EtOH) on the conformational stability and catalytic activity of G210C lipase, a laboratory-evolved mutant of Staphylococcus epidermidis AT2 lipase. Simulation studies were performed using an open-form predicted structure under 30, 40 and 50% of MtOH and EtOH at 25 °C and 45 °C. The overall enzyme structure becomes more flexible with increasing concentration of MtOH and exhibited the highest flexibility in 40% EtOH. In EtOH, the movement of the lid was found to be temperature-dependent with a noticeable shift in the lid position at 45 °C. Lid opening was evidenced at 50% of MtOH and EtOH which was supported by the increase in SASA of hydrophobic residues of the lid and catalytic triad. The active site remained mostly intact. An open-closed lid transition was observed when the structure was re-simulated in water. Experimental evaluation of the lipase stability showed that the half-life reduced when the enzyme was treated with 40% (v/v) and 50% (v/v) of EtOH and MtOH respectively. The finding implies that a high concentration of alcohol and elevated temperature can induce the lid opening of lipase which could be essential for the activation of the enzyme, provided that the catalytic performance in the active site is not compromised.Communicated by Ramaswamy H. Sarma.

The research was undertaken to assess the antidiabetic activity of rosiridin in the streptozotocin (STZ)-induced diabetic model. Type 2 diabetes mellitus was elicited chemically in experimental animals using STZ (60 mg/kg, i.p.). Experimental rats were arbitrarily allocated to normal control, rosiridin perse, diabetic control, and STZ + rosiridin groups. After the confirmation of diabetes, rosiridin (10 mg/kg) was given orally to the experimental animals for 30 days. Various anti-diabetic (blood glucose, insulin), hypolipidemic, anti-inflammatory (Nuclear factor kappa B, tumour necrosis factor-α, interleukin beta (IL-1β), and IL-6), antioxidant (and malondialdehyde level, hepatic function and others markers (ALT, AST, adiponectin, and FNDC5) and histopathological indices of injury were evaluated. In addition, the rosinidin was docked into the active site of NF-Kβ (1SVC), FNDC5 (4LSD) and adiponectin (5LXG) proteins with AutoDock tools. MD simulations were carried out for the complexes of rosiridin with NF-Kβ, myokine and human adiponectin receptor 1. Rosiridin treatment restored the biochemical parameters and preserved the histopathological building of the pancreas as compared to the diabetic rats. Histopathological analysis of the pancreas confirmed that rosiridin antidiabetic efficacy in the STZ-induced diabetes mellitus model. The 5LXG_rosinidin showed favourable affinity with the best binding energies at -7.534 kcal/mol. MD simulations were carried out for the complexes of rosiridin with NF-Kβ, myokine and human adiponectin receptor 1, the complex of myokine and rosiridin exhibited the most stable complex. Rosiridin may exhibit considerable anti-diabetic activity in the STZ-induced diabetes mellitus model.Communicated by Ramaswamy H. Sarma.

Cobalt(II) complexes of biphenyl-2-ol of composition, CoCl_2-n(OC₆H₄C₆H₅-2)_n(H₂O)₄ (where n = 1 or 2), were prepared by reacting cobaltous(II) chloride with equi- and bimolar ratios of sodium salt of biphenyl-2-ol. The structural characterization of the synthesized complexes was accomplished by NMR, FTIR, thermogravimetry (TGA), high resolution mass spectroscopy (HRMS), electronic spectroscopic techniques coupled with density functional theory (DFT). The stability of the complexes in different pH media of solvent was studied. Chemical reactivity parameters of the newly synthesized complexes, computed using DFT, indicated greater reactivity of complex 2 over complex 1 and free ligand as indicated by its low HOMO-LUMO energy gap corresponding to 1.71 eV. Molecular docking (MD) studies were carried out in order to study the binding affinities between amino acid residues of DNA duplex (PDB ID: 1BNA) and SARS-CoV-2 (PDB ID: 7T9K) with newly synthesized complexes. Complex 2 has shown promising antivirus behaviour with an inhibition constant value of 0.0423 µmol^-1 with amino acid residues of SARS-CoV-2 virus. Toxicity of the complexes was predicted using ProTox-II online server. Antibacterial studies have indicated the complexes to exhibit greater efficacy than the free ligand, while the antioxidant activities have suggested them to display enhanced antioxidant behaviour as compared to reference compounds.Communicated by Ramaswamy H. Sarma.

The severity of the influenza virus infection is largely determined by its ability to invade the human host receptor. This critical step is conducted by utilizing hemagglutinin (HA) due to its binding with sialic acid 2,6 (SA). Though 18 subtypes (H1-H18) of HA have been identified, the most efficient one for conducting the host entry has not yet been resolved. This study aims to assess the severity of infections for HA variants by conducting a comparative docking of H1-H18 with the human SA receptor. Eighteen viral 3D structures were retrieved, minimized, and optimized for docking with human SA. In all retrieved structures, five conserved amino acid residues were selected for docking with human SA. Special protein grids were prepared by locating these five residues in the 18 selected subtypes. Results showed that H3 and H8 exerted the highest standard precision and extra precision docking scores, and the highest binding affinities with the human SA, respectively. Phylogenetic analyses confirmed the actual positioning of the selected 3D structures and showed these docked structures belonged to their usual classes due to the extremely close distances found in each docked subtype compared with its corresponding non-docked structures. H8-SA showed slightly better RMSD and SASA values than H3-SA, while H3-SIA showed more favourable radius of gyration scores than H8-SIA in the majority of the simulation period. Due to the highest affinity of binding of H3 and H8 with the human receptor, special caution should be exercised regarding any possible outbreak mediated by these subtypes in human populations. However, it is important to acknowledge a limitation inherent to the computational approach; it may hold relative rather than absolute significance. Further research is needed to deepen our understanding of the intricate interplay between HA variants and the host receptor, taking into account the broader context of viral infection dynamics.Communicated by Ramaswamy H. Sarma.

The emergence of drug-resistant strains motivate researchers to find new innovative anti-IAV candidates with a different mode of action. In this work, molecular modelling strategies, such as 2D-QSAR, 3D-QSAR, molecular docking, molecular dynamics, FMOs, and ADMET were applied to some substituted indoles as IAV inhibitors. The best-developed 2D-QSAR models, MLR (Q² = 0.7634, R²_train = 0.8666) and ANN[4-3-1] (Q² = 0.8699, R²_train = 0.8705) revealed good statistical validation for the inhibitory response predictions. The 3D-QSAR models, CoMFA (Q² = 0.504, R²_train = 0.805) and CoMSIA/SEDHA (Q² = 0.619, R²_train = 0.813) are selected as the best 3D models following the global thresholds. In addition, the contour maps generated from the CoMFA and CoMSIA models illustrate the relationship between the molecular fields and the inhibitory effects of the studied molecules. The results of the studies led to the design of five new molecules (24a-e) with enhanced anti-IAV activities and binding potentials using the most active molecule (24) as the template scaffold. The conformational stability of the best-designed molecules with the NA protein showed hydrophobic and H-bonds with the key residues from the molecular dynamics simulations of 100 ns. Furthermore, the global reactivity indices from the DFT calculations portrayed the relevance of 24c in view of its smaller band gap as also justified by our QSAR and molecular simulation studies.Communicated by Ramaswamy H. Sarma.

Plumbago zeylanica is an important plant used in the Ayurvedic system of medicine for the treatment of hemorrhoids or piles. Despite its clinical uses, its molecular mechanism, for ameliorating hemorrhoids is not yet explored. Hence, the present study evaluated the plausible molecular mechanisms of P. zeylanica in the treatment of hemorrhoids using network pharmacology and other in silico analysis. Network pharmacology was carried out by protein, GO, and KEGG enrichment analysis. Further ADME/T, molecular docking and dynamics studies of the resultant bioactive compounds of P. zeylanica with the regulated proteins were evaluated. Results of the network pharmacology analysis revealed that the key pathways and plausible molecular mechanisms involved in the treatment effects of P. zeylanica on hemorrhoids are cell migration, proliferation, motility, and apoptosis which are synchronized by cancer, focal adhesion, and by signalling relaxin, Rap1, and calcium pathways which indicates the involvement of angiogenesis and vasodilation which are the characteristic features of hemorrhoids. Further, the molecular docking and dynamics studies revealed that the bio active ingredients of P. zeylanica strongly bind with the key target proteins in the ambiance of hemorrhoids. Hence, the study revealed the mechanism of P. zeylanica in ameliorating hemorrhoids.Communicated by Ramaswamy H. Sarma.