Biomedical subjects

Richard A Bryce

Publications and source records attributed to Richard A Bryce.

9 recordsLinked to original sources

PubMed2006

Benzoic acid and pyridine derivatives as inhibitors of Trypanosoma cruzi trans-sialidase.

Benzoic acid and pyridine derivatives inhibit recombinant trans-sialidase from Trypanosoma cruzi with I50 values between 0.4 and 1mM. The best compounds, 4-acetylamino-3-hydroxymethylbenzoic acid and 5-acetylamino-6-aminopyridine-2-carboxylic acid, provide new leads to inhibitors not containing the synthetically complex sialic acid structure. The weak inhibition by such compounds contrasts with their much stronger inhibition of neuraminidase from Influenza virus.

Animals↗

PubMed2006

In silico identification and biochemical characterization of novel inhibitors of NQO1.

From in silico docking and COMPARE analysis, novel inhibitors of human NAD(P)H quinone oxidoreductase (NQO1) have been identified from the NCI compound database, the most potent of which has an observed IC(50) of 0.7muM. The inhibitors exhibit a diverse range of scaffolds. The ability of docking calculations to predict experimentally determined binding affinities for NQO1 is discussed, considering the influence of target flexibility and scoring function.

Amino Acid Sequence↗

PubMed2006

Exploring reaction pathways with transition path and umbrella sampling: application to methyl maltoside.

The transition path sampling (TPS) method is a powerful approach to study chemical reactions or transitional properties on complex potential energy landscapes. One of the main advantages of the method over potential of mean force methods is that reaction rates can be directly accessed without knowledge of the exact reaction coordinate. We have investigated the complementary nature of these two differing approaches, comparing transition path sampling with the weighted histogram analysis method to study a conformational change in a small model system. In this case study, the transition paths for a transition between two rotational conformers of a model disaccharide molecule, methyl beta-D-maltoside, were compared with a free energy surface constrained by the two commonly used glycosidic (phi,psi) torsional angles. The TPS method revealed a reaction channel that was not apparent from the potential of mean force method, and the suitability of phi and psi as reaction coordinates to describe the isomerization in vacuo was confirmed by examination of the transition path ensemble. Using both transition state theory and transition path sampling methods, the transition rate was estimated. We have estimated a characteristic time between transitions of approximately 160 ns for this rare isomerization event between the two conformations of the carbohydrate. We conclude that transition path sampling can extract subtle information about the dynamics not apparent from the potential of mean force method. However, in calculating the reaction rate, the transition path sampling method required 27.5 times the computational effort than was needed by the potential of mean force method.

Algorithms↗

PubMed2006

Molecular dynamics simulation of monoalkyl glycoside micelles in aqueous solution: influence of carbohydrate headgroup stereochemistry.

Comparative molecular dynamics simulations of n-octyl-beta-D-galactopyranoside (beta-C8Gal) and n-octyl-beta-D-glucopyranoside (beta-C8Glc) micelles in aqueous solution have been performed to explore the influence of carbohydrate stereochemistry on glycolipid properties at the atomic level. In particular, we explore the hypothesis that differences in T(m) and T(c) for beta-C8Gal and beta-C8Glc in lyotropic systems arise from a more extensive hydrogen bonding network between beta-C8Gal headgroups relative to beta-C8Glc, due to the axial 4-OH group in beta-C8Gal. Good agreement of the 13 ns micelle-water simulations with available experimental information is found. The micelles exhibit a similar shape, size, and degree of exposed alkyl chain surface area. We find net inter- and intra-headgroup hydrogen bonding is also similar for beta-C8Gal and beta-C8Glc, although n-octyl-beta-D-galactopyranoside micelles do exhibit a slightly greater degree of inter- and intra-headgroup hydrogen bonding. However, the main distinction in the calculated microscopic behavior of beta-C8Glc and beta-C8Gal micelles lies in solvent interactions, where beta-d-glucosyl headgroups are considerably more solvated (mainly at the equatorial O4 oxygen). These results agree with preceding theoretical and experimental studies of monosaccharides in aqueous solution. A number of long water residence times are found for solvent surrounding both micelle types, the largest of which are associated with surface protrusions involving headgroup clusters. Our simulations, therefore, predict differences in hydrogen bonding for the two headgroup stereochemistries, including a small difference in inter-headgroup interactions, which may contribute to the higher T(m) and T(c) values of beta-C8Gal surfactants relative to beta-C8Glc in lyotropic systems.

Carbohydrate Sequence↗

PubMed2005

Exciplex fluorescence emission from simple organic intramolecular constructs in non-polar and highly polar media as model systems for DNA-assembled exciplex detectors.

Organic intramolecular exciplexes, N-(4-dimethylaminobenzyl)-N-(1-pyrenemethyl)amine (1) and N'-4-dimethylaminonaphthyl-N-(1-pyrenemethyl)amine (2), were used as model systems to reveal major factors affecting their exciplex fluorescence, and thus lay the basis for developing emissive target-assembled exciplexes for DNA-mounted systems in solution. These models with an aromatic pyrenyl hydrocarbon moiety as an electron acceptor appropriately connected to an aromatic dimethylamino electron donor component (N,N-dimethylaminophenyl or N,N-dimethylaminonaphthyl) showed strong intramolecular exciplex emission in both non-polar and highly polar solvents. The effect of dielectric constant on the maximum wavelength for exciplex emission was studied, and emission was observed for 1 and 2 over the full range of solvent from non-polar hydrocarbons up to N-methylformamide with a dielectric constant of 182. Quantum yields were determined for these intramolecular exciplexes in a range of solvents relative to that for Hoechst 33,258. Conformational analysis of 1 was performed both computationally and via qualitative 2D NMR using (1)H-NOESY experiments. The results obtained indicated the contribution of pre-folded conformation(s) to the ground state of 1 conducive to exciplex emission. This research provides the initial background for design of self-assembled, DNA-mounted exciplexes and underpins further development of exciplex-based hybridisation bioassays.

DNA↗

PubMed2005

Aminoimidazolylmethyluracil analogues as potent inhibitors of thymidine phosphorylase and their bioreductive nitroimidazolyl prodrugs.

Thymidine phosphorylase (TP) is an important target enzyme for cancer chemotherapy because it is expressed at high levels in the hypoxic regions of many tumors and inhibitors of TP have been shown in animal model studies to inhibit angiogenesis and metastasis, and to promote tumor cell apoptosis. The 5-halo-6-[(2'-aminoimidazol-1'-yl)methyl]uracils (3, X = Cl, Br) are very potent inhibitors of E. coli and human TP with IC(50) values of approximately 20 nM when the enzyme concentration is approximately 40 nM. Their 4'-aminoimidazol-1'-yl analogues (4, X = Cl, Br) are >350-fold less active with IC(50) values of approximately 7 microM. The 5-unsubstituted analogues (3 and 4, X = H) were both less active than their 5-halo derivatives. Determination of pK(a) values and molecular modeling studies of these compounds in the active site of human TP was used to rationalize their activities. The finding that 3, X = Br has a poor pharmacokinetic (PK) profile in mice, coupled with the desire for tumor selectivity, led us to design prodrugs. The corresponding 2'-nitroimidazol-1'-ylmethyluracils (5, X = Cl, Br) are >1000-fold less active (IC(50) 22-24 microM) than their 2'-amino analogues and are reduced to the 2'-amino inhibitors (3, X = Cl, Br) by xanthine oxidase (XO). As XO is also highly expressed in many tumors, the 2'-nitro prodrugs have the potential to selectively deliver the potent 2'-aminoimidazol-1'-yl TP inhibitors into hypoxic solid tumors.

Animals↗

PubMed2005

Scoring binding affinity of multiple ligands using implicit solvent and a single molecular dynamics trajectory: application to influenza neuraminidase.

We explore a perturbative approach to calculation of binding free energy of multiple ligands, based on a single molecular dynamics simulation of a reference ligand-receptor complex and analysis via a hybrid force field/continuum model potential. The methodology is applied to prediction of relative binding free energies of 10 Influenza neuraminidase inhibitors, using Poisson-Boltzmann and generalised Born models of implicit solvent. These single-step MM-PB/SA and MM-GB/SA approaches predict the experimentally most potent ligand as first- or second-ranked according to total binding free energy. Ranking of inhibitors displays only moderate sensitivity to the choice of reference trajectory and ligand partial charge scheme. When ranked according to total electrostatic binding free energy, correlation with experiment improves (r(2) of 0.72); this may be related to underestimated first solvation shell effects by the implicit water models. Therefore, to increase the generality of this single-step approach as part of a potential computational compound optimisation strategy, further development of the treatment of short-range solvent interactions is warranted.

Binding Sites↗

PubMed2005

Molecular basis of action of HyBeacon fluorogenic probes: a spectroscopic and molecular dynamics study.

HyBeacons, novel DNA probes for ultra-rapid detection of single nucleotide polymorphisms, contain a fluorophore covalently attached via a linker group to an internal nucleotide. As the probe does not require a quencher or self-complementarity to function, this study investigates the molecular-level mechanism underlying the increase of fluorescence intensity on hybridization of HyBeacons with target DNA. Spectroscopic ultraviolet-visible and fluorimetric studies, combined with molecular dynamics simulations, indicate projection of the fluorophore moiety away from the target-probe duplex into aqueous solution, although specific linker-DNA interactions are populated. Based on evidence from this study, we propose that for HyBeacons, the mechanism of increased fluorescence on hybridization is due to disruption of quenching interactions in the single-stranded probe DNA between the fluorophore and nucleobases. Hybridization leads to an extended linker conformation, removing the fluorophore from the immediate vicinity of the DNA bases.

Base Sequence↗

PubMed2004

Molecular dynamics and free energy analysis of neuraminidase-ligand interactions.

We report molecular dynamics calculations of neuraminidase in complex with an inhibitor, 4-amino-2-deoxy-2,3-didehydro-N-acetylneuraminic acid (N-DANA), with subsequent free energy analysis of binding by using a combined molecular mechanics/continuum solvent model approach. A dynamical model of the complex containing an ionized Glu119 amino acid residue is found to be consistent with experimental data. Computational analysis indicates a major van der Waals component to the inhibitor-neuraminidase binding free energy. Based on the N-DANA/neuraminidase molecular dynamics trajectory, a perturbation methodology was used to predict the binding affinity of related neuraminidase inhibitors by using a force field/Poisson-Boltzmann potential. This approach, incorporating conformational search/local minimization schemes with distance-dependent dielectric or generalized Born solvent models, correctly identifies the most potent neuraminidase inhibitor. Mutation of the key ligand four-substituent to a hydrogen atom indicates no favorable binding free energy contribution of a hydroxyl group; conversely, cationic substituents form favorable electrostatic interactions with neuraminidase. Prospects for further development of the method as an analysis and rational design tool are discussed.

Antiviral Agents↗