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Results for “Molecular Docking Simulation”

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At least 253 records · Page 14Linked to original sources

PubMed2005

Structural basis for the GSK-3beta binding affinity and selectivity against CDK-2 of 1-(4-aminofurazan-3yl)-5-dialkylaminomethyl-1H-[1,2,3] triazole-4-carboxylic acid derivatives.

A novel structural class of glycogen synthase kinase-3beta inhibitors is modeled using quantum mechanics, automated docking, and molecular dynamics simulations. The proposed binding modes identify important hydrogen bonds and salt-bridges with the ATP-binding pocket of the kinase. The modeled complexes justify the observed structure-activity relationships and provide a structural basis for the high selectivity of these inhibitors against cyclin dependent kinase-2.

Adenosine Triphosphate↗

PubMed2005

Structural insight into the interactions of SoxV, SoxW and SoxS in the process of transport of reductants during sulfur oxidation by the novel global sulfur oxidation reaction cycle.

Microbial redox reactions involving inorganic sulfur compounds, mainly the sulfur anions, are one of the vital reactions responsible for the environmental sulfur balance. These reactions are mediated by phylogenetically diverse prokaryotes, some of which also take part in the extraction of metal ions from their sulfur containing ores. These sulfur oxidizers oxidize inorganic sulfur compounds like sulfide, thiosulfate etc. to produce reductants that are used for carbon dioxide fixation or in respiratory electron transfer chains. The sulfur oxidizing gene cluster (sox) of alpha-Proteobacteria comprises of at least 15 genes, forming two transcriptional units, viz., soxSR and soxVWXYZABCDEFGH. SoxV is known to be a CcdA homolog involved in the transport of reductants from cytoplasm to periplasm. SoxW and SoxS are periplasmic thioredoxins, which (SoxW) interact with SoxV and thereby help in the redox reactions. We have employed homology modeling to construct the three-dimensional structures of the SoxV, SoxW and SoxS proteins from Rhodovulum sulfidophilum. With the help of docking and molecular dynamics simulations we have identified the amino acid residues of these proteins involved in the interaction. The probable biochemical mechanism of the transport of reductants through the interactions of these proteins has also been investigated. Our study provides a rational basis to interpret the molecular mechanism of the biochemistry of sulfur anion oxidation reactions by these ecologically important organisms.

Alphaproteobacteria↗

PubMed2002

Nitrophenyl derivatives as aldose reductase inhibitors.

Nitrophenyl derivatives were recently discovered as a new class of ALR2 inhibitors by means of docking and database screening of the National Cancer Institute database of organic molecules. The nitro group was predicted to bind to the Tyr48 and His110 active site residues of the enzyme, the site where acidic ALR2 inhibitors such as carboxylic acids bind in their anionic form. Given the novelty of these compounds, we decided to expand their structure-activity relationships by synthesizing and testing a series of derivatives and the corresponding compounds having a carboxylic group instead of the nitro moiety; the results obtained were rationalized by means of docking and molecular dynamics simulations. On the whole there is an agreement between inhibitory data and the results of molecular modeling experiments, supporting the hypothesized binding mode of these compounds.

Aldehyde Reductase↗

PubMedDate not supplied

Modeling the structural basis of human CCR5 chemokine receptor function: from homology model building and molecular dynamics validation to agonist and antagonist docking.

This article describes the construction and validation of a three-dimensional model of the human CCR5 receptor using a homology-based approach starting from the X-ray structure of the bovine rhodopsin receptor. The reliability of the model is assessed through molecular dynamics and docking simulations using both natural agonists and a synthetic antagonist. Some important structural and functional features of the receptor cavity and the extracellular loops are identified, in agreement with data available from site-directed mutagenesis. The results of this study help to explain the structural basis for the recognition, activation, and inhibition processes of CCR5 and may provide fresh insights for the design of HIV-1 entry blockers.

CCR5 Receptor Antagonists↗

PubMed1998

Conformational requirements of suramin to target angiogenic growth factors.

The conformational requirements of suramin for its binding to basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) were examined by molecular modeling and docking simulations using the conformational features of suramin determined by the present proton nuclear magnetic resonance (1H-NMR) studies and the crystal structures of growth factors reported previously. The assignment of resonances of suramin to individual protons was accomplished by the combined analysis of the coupling constants, two-dimensional correlated spectroscopy (COSY) and nuclear Overhauser effect spectroscopy (NOESY). The NOESY data obtained for suramin were utilized in a conformational search algorithm with constraints to generate a family of conformers which were further refined by restrained energy minimization. A family of nine conformers generated by restrained modeling falls primarily into one of two categories, either the conformer's two naphthyl rings are far apart, approximately 28-30 A, from one another or the conformer's two naphthyl rings are relatively close, approximately 16-18 A. The NMR data provide evidence for the presence of more than one conformer in solution. The modeling and docking simulation studies suggest that suramin binds efficiently to bFGF and PDGF by an induced-fit mechanism, wherein suramin complements bFGF or PDGF by adjusting its conformational freedom around the two pairs of single bonds that link the middle phenyl rings to the secondary amide backbone. The interaction of suramin with bFGF or PDGF primarily involves ion-pair, hydrophobic and hydrogen bonding interactions, in addition to van der Waals' contacts. The results indicate that suramin not only sterically blocks the receptor binding loop of the growth factors, but also competes for the binding sites of agonists such as heparin. The results suggest that suramin's propensity to bind to several polypeptides of varying size and structure is due to its conformational flexibility. Collectively, the data emphasize that conformationally constrained suramin analogs that selectively and competitively target angiogenic growth factors could be designed to reduce non-specific binding and, accordingly, toxicity.

Journal Article↗

PubMed2002

Molecular docking studies of a group of hydroxamate inhibitors with gelatinase-A by molecular dynamics.

We have performed docking and molecular dynamics simulations of hydroxamates complexed with human gelatinase-A (MMP-2) to gain insight into the structural and energetic preferences of these inhibitors. The study was conducted on a selected set of eleven compounds with variation in structure and activity. Molecular dynamics simulations were performed at 300 K for 100 ps with equilibration for 50 ps. The structural analyses of the trajectories indicate that the coordinate bond interactions, the hydrogen bond interactions, the van der Waals interactions as well as the hydrophobic interactions between ligand and receptor are responsible simultaneously for the preference of inhibition and potency. The ligand hydroxamate group is coordinated to the catalytic zinc ion and form stable hydrogen bonds with the carbonyl oxygen of Gly 162. The P1' group makes extensive van der Waals and hydrophobic contacts with the nonpolar side chains of several residues in the S1' subsite, including Leu 197, Val 198, Leu 218 and Tyr 223. Moreover, four to eight hydrogen bonds between hydroxamates and MMP-2 are formed to stabilize the inhibitors in the active site. Compared with the P2' and P3' groups, the P1' groups of inhibitors are oriented regularly, which is produced by the restrain of the S1' subsite. From the relationship between the length of the nonpolar P1' group and the biological activity, we confirm that MMP-2 has a pocket-like S1' subsite, not a channel-like S1' subsite proposed by Kiyama (Kiyama, R. et al., J. Med. Chem. 42 (1999), 1723). The energetic analyses show that the experimental binding free energies can be well correlated with the interactions between the inhibitors and their environments, which could be used as a simple score function to evaluate the binding affinities for other similar hydroxamates. The validity of the force field parameters and the MD simulations can be fully testified by the satisfactory agreements between the experimental structure-activity relationship and the information from the structural and energetic analyses. The information generated from the predicted complexes should be useful for further work in the area of structure-based design of new compounds.

Binding Sites↗

PubMed2000

Novel carbohydrate binding site recognizing blood group A and B determinants in a hybrid of cholera toxin and Escherichia coli heat-labile enterotoxin B-subunits.

The B-subunits of cholera toxin (CTB) and Escherichia coli heat-labile enterotoxin (LTB) are structurally and functionally related. However, the carbohydrate binding specificities of the two proteins differ. While both CTB and LTB bind to the GM1 ganglioside, LTB also binds to N-acetyllactosamine-terminated glycoconjugates. The structural basis of the differences in carbohydrate recognition has been investigated by a systematic exchange of amino acids between LTB and CTB. Thereby, a CTB/LTB hybrid with a gain-of-function mutation resulting in recognition of blood group A and B determinants was obtained. Glycosphingolipid binding assays showed a specific binding of this hybrid B-subunit, but not CTB or LTB, to slowly migrating non-acid glycosphingolipids of human and animal small intestinal epithelium. A binding-active glycosphingolipid isolated from cat intestinal epithelium was characterized by mass spectrometry and proton NMR as GalNAcalpha3(Fucalpha2)Galbeta4(Fucalpha3)Glc NAcbeta3Galbeta4Glc NAcbeta3Galbeta4Glcbeta1Cer. Comparison with reference glycosphingolipids showed that the minimum binding epitope recognized by the CTB/LTB hybrid was Galalpha3(Fucalpha2)Galbeta4(Fucalpha3)GlcNAc beta. The blood group A and B determinants bind to a novel carbohydrate binding site located at the top of the B-subunit interfaces, distinct from the GM1 binding site, as found by docking and molecular dynamics simulations.

ABO Blood-Group System↗

PubMed2003

Characterization of endostatin binding to heparin and heparan sulfate by surface plasmon resonance and molecular modeling: role of divalent cations.

Endostatin (20 kDa) is a C-terminal proteolytic fragment of collagen XVIII that is localized in vascular basement membrane zones in various organs. It binds zinc, heparin/heparan sulfate, laminin, and sulfatides and inhibits angiogenesis and tumor growth. Here we determined the kinetics and affinity of the interaction of endostatin with heparin/heparan sulfate and investigated the effects of divalent cations on these interactions and on the biological activities of endostatin. The binding of human recombinant endostatin to heparin and heparan sulfate was studied by surface plasmon resonance using BIAcore technology and further characterized by docking and molecular dynamics simulations. Kinetic data, evaluated using a 1:1 interaction model, showed that heparan sulfate bound to and dissociated from endostatin faster than heparin and that endostatin bound to heparin and heparan sulfate with a moderate affinity (K(D) approximately 2 microm). Molecular modeling of the complex between endostatin and heparin oligosaccharides predicted that, compared with mutagenesis studies, two further arginine residues, Arg(47) and Arg(66), participated in the binding. The binding of endostatin to heparin and heparan sulfate required the presence of divalent cations. The addition of ZnCl(2) to endostatin enhanced its binding to heparan sulfate by approximately 40% as well as its antiproliferative effect on endothelial cells stimulated by fibroblast growth factor-2, suggesting that this activity is mediated by the binding of endostatin to heparan sulfate. In contrast, no increase in the antiangiogenic and anti-proliferative activities of endostatin promoted by vascular endothelial growth factor was observed upon the addition of zinc.

Cations, Divalent↗

PubMed2006

N-methylpurine DNA glycosylase and 8-oxoguanine dna glycosylase metabolize the antiviral nucleoside 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole.

The rapid in vivo degradation of the potent human cytomegalovirus inhibitor 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (BDCRB) compared with a structural L-analog, maribavir (5,6-dichloro-2-(isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole), has been attributed to selective glycosidic bond cleavage. An enzyme responsible for this selective BDCRB degradation, however, has not been identified. Here, we report the identification of two enzymes, 8-oxoguanine DNA glycosylase (OGG1) and N-methylpurine DNA glycosylase (MPG), that catalyze N-glycosidic bond cleavage of BDCRB and its 2-chloro homolog, 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole, but not maribavir. To our knowledge, this is the first demonstration that free nucleosides are substrates of OGG1 and MPG. To understand how these enzymes might process BDCRB, docking and molecular dynamics simulations were performed with the native human OGG1 crystal coordinates. These studies showed that OGG1 was not able to bind a negative control, guanosine, yet BDCRB and maribavir were stabilized through interactions with various binding site residues, including Phe319, His270, Ser320, and Asn149. Only BDCRB, however, achieved orientations whereby its anomeric carbon, C1', could undergo nucleophilic attack by the putative catalytic residue, Lys249. Thus, in silico observations were in perfect agreement with experimental observations. These findings implicate DNA glycosylases in drug metabolism.

Antiviral Agents↗

PubMed2005

Orientational dynamics and dye-DNA interactions in a dye-labeled DNA aptamer.

We report the picosecond and nanosecond timescale rotational dynamics of a dye-labeled DNA oligonucleotide or "aptamer" designed to bind specifically to immunoglobulin E. Rotational dynamics in combination with fluorescence lifetime measurements provide information about dye-DNA interactions. Comparison of Texas Red (TR), fluorescein, and tetramethylrhodamine (TAMRA)-labeled aptamers reveals surprising differences with significant implications for biophysical studies employing such conjugates. Time-resolved anisotropy studies demonstrate that the TR- and TAMRA-aptamer anisotropy decays are dominated by the overall rotation of the aptamer, whereas the fluorescein-aptamer anisotropy decay displays a subnanosecond rotational correlation time much shorter than that expected for the overall rotation of the aptamer. Docking and molecular dynamics simulations suggest that the low mobility of TR is a result of binding in the groove of the DNA helix. Additionally, associated anisotropy analysis of the TAMRA-aptamer reveals both quenched and unquenched states that experience significant coupling to the DNA motion. Therefore, quenching of TAMRA by guanosine must depend on the configuration of the dye bound to the DNA. The strong coupling of TR to the rotational dynamics of the DNA aptamer, together with the absence of quenching of its fluorescence by DNA, makes it a good probe of DNA orientational dynamics. The understanding of the nature of dye-DNA interactions provides the basis for the development of bioconjugates optimized for specific biophysical measurements and is important for the sensitivity of anisotropy-based DNA-protein interaction studies employing such conjugates.

Anisotropy↗

PubMed2026

CCT2 defines a highly cisplatin-resistant and poor-prognosis subtype of lung adenocarcinoma.

Cisplatin-based chemotherapy is a standard treatment for lung adenocarcinoma (LUAD), yet acquired cisplatin resistance remains a marked cause of treatment failure. The molecular mechanisms driving cisplatin resistance in LUAD have not been fully elucidated. The present study integrated bulk transcriptomic data, genomic mutation profiles and single-cell RNA sequencing data to systematically investigate cisplatin resistance in LUAD. Resistance-associated genes were identified through differential expression, survival analysis and database integration. Unsupervised clustering was used to define cisplatin resistance-associated subtypes. Functional characteristics were explored using pathway enrichment, immune infiltration, tumor mutation burden and weighted gene co-expression network analysis. A machine learning framework incorporating 101 algorithms was applied to identify key genes and construct a prognostic model. Single-cell analyses and in vitro experiments were performed to validate the biological role of the core gene. Molecular docking and molecular dynamics simulations were conducted to identify potential therapeutic compounds. A total of two molecular subtypes with distinct cisplatin resistance levels and prognostic outcomes were identified. The high-resistance subtype exhibited enhanced cell cycle activity, DNA repair signaling and immune heterogeneity. Machine learning analysis revealed a five-gene signature, with chaperonin-containing TCP1 subunit 2 (CCT2) emerging as a key regulator of cisplatin resistance. Single-cell analyses showed that CCT2 was predominantly enriched in resistant epithelial cell subpopulations. Functional experiments demonstrated that CCT2 knockdown significantly inhibited cell proliferation and enhanced cisplatin sensitivity in LUAD cell lines. A number of candidate compounds targeting CCT2 exhibited stable binding in silico. The present findings identified CCT2 as a key mediator of cisplatin resistance in LUAD and provided potential therapeutic strategies to overcome chemotherapy resistance.

chaperonin-containing TCP-1 subunit 2↗

PubMed2007

[Receptor-ligand docking simulation for membrane proteins].

Protein structure-based molecular design using the computational techniques of protein structure prediction, ligand docking, and virtual screening is an integral part of drug discovery for limiting the application of the structure-based approach to target proteins such as G-protein-coupled receptors (GPCRs). GPCRs play an important role in living organisms and are of major interest to the pharmaceutical industry. However, structural data on ligand-binding forms for GPCRs from experiments to elucidate structural templates for docking simulations are lacking due to the difficulties associated with crystallization and crystallography. Therefore structural prediction of GPCRs in the ligand-bound state using computational methods has been introduced, but the prediction of ligand conformation onto target GPCRs is still constructed manually by human experts. We developed a molecular modeling technique for the prediction of ligand-receptor binding using comparative ligand-binding analysis (CoLBA) that not only considers interaction energy but also the similarity of interaction profiles among ligands. The advantage of CoLBA is that it can facilitate intuitive and flexible screening based on docking results when protein structures with low resolution (or theoretical models) are targeted. We applied CoLBA to ligand-binding prediction in several GPCRs. The predicted ligand-binding models were evaluated in site-directed mutagenesis experiments in collaborative research, and the enrichment rate of activated ligands was compared with random compounds in virtual screening simulations. We propose that CoLBA can be applied in large-scale modeling of ligand-receptor complexes and virtual screening for GPCRs.

Amino Acid Sequence↗

PubMed2025

Computational identification of potential antifungal targets against Claviceps purpurea via MD simulation and MM/GBSA.

Ergot alkaloids produced by the fungus Claviceps purpurea pose significant risks to agriculture and human health. This study systematically investigates the pathogenicity of C. purpurea, analyzing five strains for their proteomic profiles, which revealed genetic variability in size and GC content. We identified proteins localized in various cellular compartments, contributing to our understanding of essential cellular processes. A focus on potential drug targets led to the identification of Alpha-N-acetylglucosaminidase, a hydrolase with significant mass and functional relevance, despite not matching a UniProt entry. The 3D structure prediction confirmed its integrity, making it a suitable target for further analysis. Molecular docking identified ligands CID:51,535,944 and CID:145,242,255 with strong binding affinities to Alpha-N-acetylglucosaminidase, highlighting interactions with key residues like TRP138, ARG651. Molecular docking interactions were validated and showed consistency through MD simulation analyses with greater RMSD, RMSF and PL contacts. This research enhances our understanding of C. purpurea, offering insights into its genetic diversity and cellular mechanisms while identifying promising therapeutic targets. The findings contribute to strategies for mitigating the economic and health impacts of C. purpurea infections, paving the way for innovative interventions in sustainable agriculture.

Molecular Docking Simulation↗

PubMed2004

A computational study of the binding of propidium to the peripheral anionic site of human acetylcholinesterase.

Combined docking and molecular dynamics (MD) simulations were carried out in order to investigate the binding mode of propidium at the human acetylcholinesterase (HuAChE) peripheral site. Two different docking protocols followed by cluster analyses were performed, allowing the identification of five high-populated and low-energy configuration families. To dynamically explore the behavior of the ligand at the peripheral HuAChE binding site, six complexes (five low-energy and one high-energy) were submitted to 2.5 ns of MD simulations. The representative propidium/HuAChE binding modes were chosen on the basis of both the docking energy score and the dynamic stability of the complexes throughout the MD simulations. The most stable poses of propidium at HuAChE PAS were similar to those experimentally determined with the murine enzyme. We therefore suggest that the present modeling protocol might be used in the dynamic investigation of the interactions of a small-molecule inhibitor with a surface-like binding site of a protein. Finally, because of the biological relevance of the target studied here, the present results can be of interest for the rational design of molecules potentially useful in the treatment of the Alzheimer's disease.

Acetylcholinesterase↗

PubMed1996

Distributed automated docking of flexible ligands to proteins: parallel applications of AutoDock 2.4.

AutoDock 2.4 predicts the bound conformations of a small, flexible ligand to a nonflexible macromolecular target of known structure. The technique combines simulated annealing for conformation searching with a rapid grid-based method of energy evaluation based on the AMBER force field. AutoDock has been optimized in performance without sacrificing accuracy; it incorporates many enhancements and additions, including an intuitive interface. We have developed a set of tools for launching and analyzing many independent docking jobs in parallel on a heterogeneous network of UNIX-based workstations. This paper describes the current release, and the results of a suite of diverse test systems. We also present the results of a systematic investigation into the effects of varying simulated-annealing parameters on molecular docking. We show that even for ligands with a large number of degrees of freedom, root-mean-square deviations of less than 1 A from the crystallographic conformation are obtained for the lowest-energy dockings, although fewer dockings find the crystallographic conformation when there are more degrees of freedom.

Azepines↗

PubMed2005

Regiospecificity of human cytochrome P450 1A1-mediated oxidations: the role of steric effects.

Cytochrome P450 1A1 oxidizes a diverse range of substrates, including the procarcinogenic xenobiotic benzo[a]pyrene (B[a]P) and endogenous fatty acid precursors of prostaglandins, such as arachidonic acid (AA) and eicosapentaenoic acid (EA). We have investigated the extent to which enzyme-substrate interactions govern regio- and stereoselectivity of oxidation of these compounds by using docking and molecular dynamics (MD) simulations to examine the likelihood of substrate oxidation at various sites. Due to structural differences between the substrates analyzed, B[a]P and its diols (planar, rigid), and the fatty acids AA and EA (long, flexible), different docking strategies were required. B[a]P, B[a]P-7,8-diols, (+) 7S,8S- and (-) 7R,8R-diols, were docked into the active site of a homology model of P450 1A1 using an automated routine, Affinity (Accelrys, San Diego, CA). AA and EA, on the other hand, required a series of restrained MD simulations to obtain a variety of productive binding modes. All complexes were evaluated by MD-based in silico site scoring to predict product profiles based on certain geometric criteria, such as angle and distance of a given substrate atom from the ferryl oxygen. For all substrates studied, the in vitro profiles were generally reflected by the in silico scores, which suggests that steric factors play a key role in determining regiospecificity in P450 1A1-mediated oxidations. We have also shown that molecular dynamics simulations may be very useful in determination of product profiles for structurally diverse substrates of P450 enzymes.

Binding Sites↗

PubMed2026

An immunoinformatics-based multi-epitope vaccine candidate confers cross-protection against two Actinobacillus pleuropneumoniae serovars.

Porcine contagious pleuropneumonia (PCP) is caused by Actinobacillus pleuropneumoniae (APP) and inflicts heavy economic losses on the swine industry. However, existing inactivated vaccines provide limited cross-protection, highlighting the need for improved vaccine strategies. In this study, we combined pangenome analysis with subtractive proteomics to screen the APP core genome and identified 11 potential antigens. Seven of them showed immunoreactivity by ELISA and Western blotting. These antigens, together with the ApxI-III toxins, were used for T and B cell epitope prediction. On this basis, a multi-epitope fusion protein MVAPP was constructed. In silico molecular docking with swine immune receptors and immune simulations suggested that MVAPP has the potential to induce immune responses. In the mouse model, that MVAPP elicited specific antibody responses, shifted the splenic T-cell subset distribution toward CD4+ T cells, and provided partial protection against challenge with strains from two serovars. In conclusion, MVAPP represents a potential multi-epitope vaccine candidate for further development against APP.

Animals↗

PubMed2005

CAMM techniques for the prediction of the mechanical properties of tendons and ligaments nanostructures.

Theoretical prediction of the mechanical properties of soft tissues usually relies on a top-down approach; that is analysis is gradually refined to observe smaller structures and properties until technical limits are reached. Computer-Assisted Molecular Modeling (CAMM) allows for the reversal of this approach and the performance of bottom-up modeling instead. The wealth of available sequences and structures provides an enormous database for computational efforts to predict structures, simulate docking and folding processes, simulate molecular interactions, and understand them in quantitative energetic terms. Tendons and ligaments can be considered an ideal arena due to their well defined and highly organized architecture which involves not only the main structural constituent, the collagen molecule, but also other important molecular "actors" such as proteoglycans and glycosaminoglycans. In this ideal arena each structure is well organized and recognizable, and using the molecular modeling tool it is possible to evaluate their mutual interactions and to characterize their mechanical function. Knowledge of these relationships can be useful in understanding connective tissue performance as a result of the cooperation and mutual interaction between different biological structures at the nanoscale.

Algorithms↗