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At least 19 recordsLinked to original sources
PubMed2004

Disialogangliosides and their interaction with cholera toxin - investigation by molecular modeling, molecular mechanics and molecular dynamics.

Molecular mechanics and molecular dynamics studies are performed to investigate the conformational preference of cell surface disialogangliosides (GD1A, GD1B and GD3) in aqueous environment. The molecular mechanics calculation reveals that water mediated hydrogen bonding network plays a significant role in the structural stabilization of GD1A, GD1B and GD3. These water mediated hydrogen bonds not only exist between neighboring residues but also exist between residues that are separated by 2 to 3 residues in between. The conformational energy difference between different conformational states of gangliosides correlates very well with the number of water mediated and direct hydrogen bonds. The spatial flexibility of NeuNAc of gangliosides at the binding site of cholera toxin is worked out. The NeuNAc has a limited allowed eulerian space at the binding site of Cholera Toxin (2.4%). The molecular modeling, molecular mechanics and molecular dynamics of disialoganglioside-cholera toxin complex reveal that cholera toxin can accommodate the disialoganglioside GD1A in three different modes. A single mode of binding is permissible for GD1B and GD3. Direct and water mediated hydrogen bonding interactions stabilizes these binding modes and play an essential role in defining the order of specificity for different disialogangliosides towards cholera toxin. This study not only provides models for the disialoganglioside-cholera toxin complexes but also identifies the NeuNAc binding site as a site for design of inhibitors that can restrict the pathogenic activity of cholera toxin.

Binding Sites↗
PubMed2006

Conformations of higher gangliosides and their binding with cholera toxin - investigation by molecular modeling, molecular mechanics, and molecular dynamics.

Molecular mechanics and molecular dynamics studies are performed to investigate the conformational preference of cell surface higher gangliosides (GT1A and GT1B) and their interaction with Cholera Toxin. The water mediated hydrogen bonding network exists between sugar residues in gangliosides. An integrated molecular modeling, molecular mechanics, and molecular dynamics calculation of cholera toxin complexed with GT1A and GT1B reveal that, the active site of cholera toxin can accommodate these higher gangliosides. Direct and water mediated hydrogen bonding interactions stabilize these binding modes and play an essential role in defining the order of specificity for different higher ganglioside towards cholera toxin. This study identifies that the binding site of cholera toxin is shallow and can accommodate a maximum of two NeuNAc residues. The NeuNAc binding site of cholera toxin may be crucial for the design of inhibitors that can prevent the infection of cholera.

Binding Sites↗
PubMed2006

Adsorption equilibria of hydrocarbons in the structure of the reforming catalyst: molecular modeling.

Molecular modeling was used to analyze the phenomena involved in the sorption of hydrocarbons by the Pt/Al2O3 reforming catalyst. The interactions between the atoms of the catalyst structure and the molecules of the model reforming compounds were described in terms of the universal forcefield. Making use of the GCMC algorithms, the adsorption isotherms for the reagents in the catalytic system and the temperature dependence of the Henry constant were determined. The research has produced the following major findings: the amount of the hydrocarbon molecules adsorbed rises with increasing pressure and decreasing temperature, and the adsorption isotherm for toluene has a characteristic plot as compared to the isotherms of the other hydrocarbons studied. Mass cloud analysis has revealed a favorable effect of platinum on adsorption in the catalyst model.

Adsorption↗
PubMed1997

Collagen-based structures containing the peptoid residue N-isobutylglycine (Nleu): conformational analysis of Gly-Nleu-Pro sequences by 1H-NMR and molecular modeling.

Molecular modeling and 1H-NMR were employed to study the structure and stability of collagen-like triple helices composed of Gly-Nleu-Pro repeats. The compounds studied include the acetyl analogs Ac-(Gly-Nleu-Pro)n-NH2 (where n = 1, 3, 6, and 10) and the KTA conjugates KTA-[Gly-(Gly-Nleu-Pro)n-NH2]3 (where n = 3 and 6 and KTA denotes the Kemp triacid). The presence of collagen-like assembled structures is supported by a consistent set of experimental observations, which include the appearance of a distinct set of resonances, low hydrogen-exchange rates for Gly NH, cooperative melting transition, and observation of several interchain NOEs. Using 1H-NMR, the triple helicity was monitored as a function of chain length, template, and temperature. These studies show that (Gly-Nleu-Pro)n sequences have a somewhat higher triple-helical propensity than (Gly-Pro-Nleu)n sequences. In addition, our investigations have shown that unlike the triple helices composed of Gly-Pro-Nleu repeats those composed of Gly-Nleu-Pro repeats can access conformations in which the Nleu side chains are arrayed between Pro residues belonging to different triple-helix cross sections. These structural features may serve as a basis for free energy computations and for the study of higher-order structures such as collagen-like fibrils containing peptoid moities.

Amino Acid Sequence↗
PubMed2000

[Immunomodulator structure-activity relationships: contribution of molecular modeling].

Molecular modeling used to compare 64 immunostimulant compounds with pyrrolie quinolein or purine nuclei has pointed out that a common spatial structure is found in most of the active compounds. An additional study of immunostimulants (levamisole, muramyldipeptide) or immunosuppressive molecules (rapamycin) was performed. A common pharmacophore was found on every studied compound. It was composed of three neighboring electroattractive atoms and a further fourth atom. The favorable conformation of rapamycin for immunosuppressive action, which is not the more stable conformation, could explain the loss of its activity, or those of related macrolides, when some minor chemical modifications are tested. These findings validate the proposed concept and provide a view of the mechanism of action of most of the immunomodulator compounds for preparing novel compounds

Adjuvants, Immunologic↗
PubMed2005

Heme peroxidase clothing and inhibition with polyphenolic substances revealed by molecular modeling.

Molecular modeling techniques were applied to study oligomeric derivatives of phenols, which are produced during peroxidase-catalyzed oxidation. The interaction of substrates and oligomers with Arthromyces ramosus peroxidase (ARP) was analyzed by docking and molecular dynamics methods. The most possible interaction site of oligomers is the active center of the peroxidase. The affinity of oligomers increases with increasing length of oligomers. However, the complexed oligomers produce non-productive complexes with the peroxidase. Molecular dynamics studies showed that oligomer-peroxidase complexes are stable. It seems likely that strong and stable, but non-productive docking of the oligomers determinates peroxidase inhibition during the reaction by preventing the access of regular substrates to the active center of the enzyme.

Binding Sites↗
PubMed2005

Molecular modeling and molecular dynamics simulation of the human A2B adenosine receptor. The study of the possible binding modes of the A2B receptor antagonists.

A molecular model of the human A(2B) adenosine receptor containing seven transmembrane alpha helices connected by three intracellular and three extracellular hydrophilic loops had been constructed. A molecular docking of seven structurally diverse xanthine antagonists of the A(2B) receptor was performed, and the differences in their binding modes were investigated. The 1 ns molecular dynamics (MD) simulations of several obtained ligand-receptor complexes inserted into the phospholipid bilayer were carried out. The conformational changes of the A(2B) receptor occurring during MD simulations were explored, and the stable binding modes of the studied antagonists were determined. According to the models presented in this work, the involvement of the His251, Asn282, Ser92, Thr89, and some aromatic residues in ligand recognition was determined. The obtained binding modes of the A(2B) antagonists demonstrate good agreement with the site-directed mutagenesis data.

Adenosine A2 Receptor Antagonists↗
PubMed1992

Prediction of the structure of the Y+.R-.R(+)-type DNA triple helix by molecular modelling.

Molecular mechanics has been used to predict the structure of the Y+.R-.R(+)-type DNA triple helix, in which a second polypurine strand binds antiparallel to the homopurine strand of a homopurine/homopyrimidine stretch of duplex DNA. From calculations on the sequence d(C)10.d(G)10.d(G)10, two likely structures emerge. One has the glycosidic torsions of the third strand bases in the anti-conformation and Hoogsteen hydrogen-bonds to the purine strand of the duplex, the other has the third strand purines in the syn orientation and uses a reverse-Hoogsteen hydrogen-bonding pattern. Despite the large structural differences between these two types of triplex, calculations performed in vacuo with a distance-dependent dielectric constant to mimic the shielding effect of solvent show them to be energetically very similar, with the latter (syn) slightly preferred. However, if explicit solvent molecules are included in the calculation, the anti conformation is found to be much preferred. This difference in the results seems to stem from an underestimation of short-range electrostatic interactions in the in vacuo simulations. When TAA or TAT base triples are substituted for the sixth CGG triple in the sequence, it is found that, for the solvated model, the third strand base of the TAA triple prefers the syn orientation while that in the TAT triple retains a preference, though reduced, for the anti conformation.

Base Sequence↗
PubMed1995

Substrate recognition by ribosome-inactivating protein studied by molecular modeling and molecular electrostatic potentials.

A computer model of dianthin 30, a type 1 ribosome-inactivating protein (RIP), is constructed by homology modeling using two known X-ray structures; a type 1 RIP, pokeweed antiviral protein (PAP), and chain A of a type 2 RIP, ricin. The 3D structure is refined by molecular dynamics and its binding site compared with those of PAP and ricin using molecular electrostatic potential mapping. The differences in the maps obtained clearly show how, despite the similarity of the topology of the binding site, differences in electrostatic potential can account for the experimentally observed differences in substrate recognition and binding. This demonstrates the potential of these techniques for guiding further experimental analyses.

Amino Acid Sequence↗
PubMed2004

Monosialogangliosides and their interaction with cholera toxin - investigation by molecular modeling and molecular mechanics.

Molecular mechanics and molecular dynamics studies are performed to investigate the conformational preference of cell surface monosialogangliosides (GM3, GM2 and GM1) in aqueous environment. Water mediated hydrogen bonding network plays a significant role in the structural stabilization of GM3, GM2 and GM1. The spatial flexibility of NeuNAc of gangliosides at the binding site of cholera toxin reveals a limited allowed eulerian space of 2.4% with a much less allowed eulerian space (1.4%) for external galactose of GM1. The molecular mechanics of monosialoganglioside-cholera toxin complex reveals that cholera toxin can accommodate the monosialogangliosides in three different modes. Direct and water mediated hydrogen bonding interactions stabilize these binding modes and play an essential role in defining the order of specificity for different monosialogangliosides towards cholera toxin. This study identifies the NeuNAc binding site as a site for design of inhibitors that can restrict the pathogenic activity of cholera toxin.

Carbohydrate Conformation↗
PubMed2005

Bioisosteric replacements of the pyrazole moiety of rimonabant: synthesis, biological properties, and molecular modeling investigations of thiazoles, triazoles, and imidazoles as potent and selective CB1 cannabinoid receptor antagonists.

Series of thiazoles, triazoles, and imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB(1) receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The thiazoles, triazoles, and imidazoles elicited in vitro( )()CB(1) antagonistic activities and in general exhibited considerable CB(1) vs CB(2) receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure-activity relationship (SAR) study revealed a close correlation between the biological results in the imidazole and pyrazole series.

Administration, Oral↗
PubMed2002

Structural analysis of human CCR2b and primate CCR2b by molecular modeling and molecular dynamics simulation.

CCR2b, a chemokine receptor for MCP-1, -2, -3, -4, plays an important role in a variety of diseases involving infection, inflammation, and/or injury, as well as being a coreceptor for HIV-1 infection. Two models of human CCR2b (hCCR2b) were generated by homology modeling and 1 ns restrained molecular dynamics (MD) simulation. In one only C113-C190 forms a disulfide bond (SS model); in another the potential C32-C277 disulfide bond was formed (2SS model). Analysis of the structures and averaged displacements of Calpha atoms of the N-terminal residues shows that the main differences between the SS and 2SS models lie in a region D25YDYGAPCHKFD36; in the extracellular part of the 2SS model the accessible surfaces of N12, F23, Y26, Y28 and F35 are obviously raised and a more stable H-bond net is formed. The potential energy of the 2SS-water assembly finally fluctuated around -43,020 kJ x mol(-1), which is about 302 kJ x mol(-1) lower than that of the SS-water assembly. All these results suggest that the 2SS model is more favorable. The CCR2b genes of 17 primates were sequenced and four CCR2b models for primates Ateles paniscus (A. pan), Hylobates leucogyneus(H. leu), Papio cynocephalus (P. cyn) and Trachypithecus francoist ( T. fra) were generated based on the 2SS model. A comparison of hCCR2b with primate CCR2b also supports the importance of the region D25YDYGAPCHKFD36. Electrostatic potential maps of human and primate CCR2b all display the dipolar characteristics of CCR2b with the negative pole located in the extracellular part and a strong positive pole in the cytoplasmic part. Based on the CCR2b model, we suggest that the main functional residues fall in the D25YDYGAPCHKFD36 region, and the negative electrostatic feature is a non-specific, but necessary, factor for ligands or gp120/CD4 binding.

Amino Acid Sequence↗
PubMed1988

Chemical carcinogenesis: from animal models to molecular models in one decade.

During the last decade, progress in chemical carcinogenesis research has been substantial, and understanding the cellular changes and molecular causes of initiation, promotion, and malignant conversion appears to be within reach. Cancer begins as a carcinogen-induced genetic change in a single cell. The interaction of a particular carcinogen with specific genetic sites results, in part, from selectivity of metabolically activated carcinogens for particular nucleosides or gene sequences. In turn, modification of the molecular structure at specific genetic loci will have tissue-specific and species-specific consequences dependent on the expression of a particular gene, its sequence, and the function of the gene product in the target cell. It is likely that inactivation of regulatory regions, genomic rearrangements, and point mutations in coding sequences all can result in an altered cell phenotype. The rasH gene (and perhaps other members of the ras gene family) appears to be a common target for coding sequence mutations in the initiation of carcinogenesis in several organ sites and species by specific carcinogens. Whatever genetic mechanisms are involved, an initiated cell phenotype common to many epithelial cell types is observed. Initiated cells have an altered program of terminal differentiation, are resistant to cytotoxic substances or show altered requirements for specific growth factors or nutrients. These cells would have a selective growth advantage in cytostatic or cytotoxic situations or under conditions favoring terminal differentiation. Tumor promoters, some acting through specific cellular receptors, produce a tissue environment conductive to the selective clonal outgrowth of the initiated cell population resulting in a clinically evident premalignant lesion. The tissue specificity for most promoters depends on the ability of a particular agent to produce the selective conditions required for the initiated phenotype of that organ. At the molecular level, phorbol ester tumor promoters bind to and activate protein kinase C and transduce signals through this second-messenger pathway. Heterogeneity in the species of protein kinase C molecule expressed by normal and initiated epidermal cells could account for the differential response pattern observed in these cell types during skin tumor promotion. Malignant conversion of benign tumors requires further genetic changes in the tumor cell. Such changes could result from inherent instability in the genome of initiated cells, from spontaneous mutations more likely to occur in the expanding population of proliferating benign tumor cells, or by additional exposure to exogenous genotoxic agents.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Structural effects on the binding of amine drugs with the diphenylmethyl functionality to cyclodextrins. II. A molecular modeling study.

Molecular modeling has been used to study the complexation between alpha, beta, or gamma-cyclodextrin (CD) and a group of amine compounds having the diphenylmethyl functionality. The computer program SYBYL 5.3 and the Tripos force field (version 5.2) were used for all the calculations. Three-dimensional structures of 13 amine compounds were built individually from their atoms, and CDs were built based on the X-ray crystallographic coordinates. The diphenylmethyl derivative-CD complexes were constructed and optimized. Based on the calculated binding energies accompanying the inclusion process, the preferred method of approach of the compounds to the cavities of the CD molecules, and the structural effects on the binding between amine compounds and three CDs were explored. The calculated binding energies exhibited a good correlation with the stability constants obtained from solution calorimetric titrations. The present study shows that for similar ligand molecules, the molecular modeling technique should enable us to visualize the structure of the inclusion complexes and will also assist us in determining the ability of a potential drug molecule to form a stable complex with CDs.

Amines↗
PubMed1996

Importance of the hydrophobic energy: structural determination of a hypoglycemic drug of the meglitinide family by nuclear magnetic resonance and molecular modeling.

The molecular structure of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionic acid (KAD-1229), a hypoglycemic drug of the meglitinide family, was studied by nuclear magnetic resonance (NMR) and molecular modeling. The results of the NMR experiments indicated that KAD-1229 existed in solution in the form of two stable conformers of equal population, called KADI and KADII in this paper. Three different molecular modelings were then applied: the classical molecular dynamics using the commercial Biosym and Hyperchem softwares and the Prot+ program, which is not based on a dynamical study but on a systematic conformational analysis of the molecule, which includes a term that allows the estimation of the hydrophobic interaction. The modeling results showed the following points. First, in contrast with classical molecular dynamics, which uses restraints from two-dimensional nuclear Overhauser effect (NOE) data, the Prot+ KAD structure provides conformations that support experimental NMR data without any external intervention. In the structures in agreement with NMR data, an important hydrophobic interaction between the phenyl cycle and the perhydroisoindole ring of KAD is observed. This interaction, which seems to play a role in the biological activity of the drug, is lost when no restraints are considered in classical molecular dynamics. Second, the difference between KADI and KADII arises mainly from slight distance geometric differences at the level of the perhydroisoindole and the phenyl rings.

Benzamides↗
PubMed2005

Characterization of binding site of closed-state KCNQ1 potassium channel by homology modeling, molecular docking, and pharmacophore identification.

This investigation was performed to assess the importance of interaction in the binding of blockers to KCNQ1 potassium using molecular modeling. This work could be considered made up by three main steps: (1) the construction of closed-state structure of KCNQ1 through homology modeling; (2) the automated docking of three blockers: IKS-142, L-735821, and BMS-IKS, using DOCK program; (3) the generation and validation of pharmacophore for KCNQ1 ligands using Catalyst/HypoGen. The obtained results highlight the hydrophobic or aromatic residues involved in S6 transmembrane domain and the base of the pore helix of KCNQ1, confirming the mutagenesis data and pharmacophore model, and giving new suggestions for the rational design of novel KCNQ1 ligands.

Amino Acid Sequence↗