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11.
Many dissimilar protein sequences fold into similar structures. A central and persistent challenge facing protein structural analysis is the discrimination between homology and convergence for structurally similar domains that lack significant sequence similarity. Classic examples are the OB-fold and SH3 domains, both small, modular beta-barrel protein superfolds. The similarities among these domains have variously been attributed to common descent or to convergent evolution. Using a sequence profile-based phylogenetic technique, we analyzed all structurally characterized OB-fold, SH3, and PDZ domains with less than 40% mutual sequence identity. An all-against-all, profile-versus-profile analysis of these domains revealed many previously undetectable significant interrelationships. The matrices of scores were used to infer phylogenies based on our derivation of the relationships between sequence similarity E-values and evolutionary distances. The resulting clades of domains correlate remarkably well with biological function, as opposed to structural similarity, indicating that the functionally distinct sub-families within these superfolds are homologous. This method extends phylogenetics into the challenging "twilight zone" of sequence similarity, providing the first objective resolution of deep evolutionary relationships among distant protein families. 相似文献
12.
13.
Theobald DS Maurer HH 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2006,842(2):76-90
The phenethylamine-derived designer drug 4-ethyl-2,5-dimethoxy-beta-phenethylamine (2C-E) was found to be mainly metabolized in rats by O-demethylation, N-acetylation, hydroxylation of the ethyl side chain at C2' or at C1' followed by oxidation at C1' to the corresponding ketone, by deamination followed by reduction to the corresponding alcohols or by oxidation to the corresponding acids, and finally combinations of these steps. Most of the metabolites were excreted in conjugated form. The authors' systematic toxicological analysis (STA) procedure using full-scan GC-MS allowed the detection of an intake of a dose of 2C-E in rat urine that corresponds to a common drug users' dose. Assuming similar metabolism, the described STA procedure should be suitable for proof of an intake of 2C-E in human urine. 相似文献
14.
Boyd HF Flynn ST Hickey DM Ife RJ Jones M Leach CA Macphee CH Milliner KJ Rawlings DA Slingsby BP Smith SA Stansfield IG Tew DG Theobald CJ 《Bioorganic & medicinal chemistry letters》2000,10(4):395-398
Starting from two weakly active hits from high throughput screening, a novel series of 2-(alkylthio)-pyrimidin-4-ones with high potency and selectivity for lipoprotein-associated phospholipase A2 has been designed. In contrast to previously known inhibitors, these have been shown to act by a non-covalent and substrate competitive mechanism. 相似文献
15.
Tendons transfer muscular forces efficiently and painlessly, facilitating joint motion. Whilst the tribology of articular cartilage is constantly explored, a poorer understanding remains of tendon lubrication and friction. This study reports experimental data describing the tribological characteristics of tendon and its surrounding tissue, before presenting an arithmetic solution to facilitate numerical modelling. The experimental characteristics of the tensile (i.e. mid-substance) and compressive (i.e. fibrocartilaginous) regions of bovine flexor tendon were investigated using a pin-on-plate tribometer, with immunofluroscence analysis describing the relative intensity and distribution of surface-bound lubricin. Arithmetic analysis considering the digital extensor tendon determined that, in physiological conditions, the tensile tendon region was able to generate elastohydrodynamic lubrication (EHL). The equivalent region of compressive tendon exhibited a higher intensity of surface-bound lubricin which, it is hypothesised, serves to minimise the increased frictional resistance due to generating only mixed or boundary lubrication regimes. Arithmetic analysis indicates that, given a more favourable biomechanical environment, this region can also generate EHL. Whilst acknowledging the limitations of transferring data from an animal model to a clinical environment, by providing the first data and equations detailing the film thicknesses and lubrication regime for these two tendon regions it is hoped that clinicians, engineers and scientists can consider improved clinical strategies to tackle both tendinopathy and tendon rupture. 相似文献
16.
Skidmore J Atcha Z Boucherat E Castelletti L Chen DW Coppo FT Cutler L Dunsdon RM Heath BM Hutchings R Hurst DN Javed S Martin S Maskell ES Norton D Pemberton DJ Redshaw S Rutter R Sehmi SS Scoccitti T Temple HE Theobald P Ward RW Wilson DM 《Bioorganic & medicinal chemistry letters》2012,22(10):3560-3563
A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement. 相似文献
17.
Many animal populations display consistent individual differences in suites of correlated behaviours. While these so called 'animal personalities' can substantially influence the ecology and evolution of populations, little is known about cross-sex correlations of behaviour and thus the potential of personality to limit sex-specific behavioural adaptations. Here, we experimentally induced sex-change in the sequentially hermaphroditic reef fish Parapercis cylindrica and demonstrate the existence of tight cross-sex correlations for two behaviours with presumed different sex-specific optima. Individuals that were relatively more active and aggressive females were found to become relatively more active and aggressive males. By identifying personality as a potential genetic constraint on the resolution of intralocus sexual conflict over behaviour, our findings have important ecological and evolutionary implications for a wide range of species. 相似文献
18.
Clarke B Demont E Dingwall C Dunsdon R Faller A Hawkins J Hussain I MacPherson D Maile G Matico R Milner P Mosley J Naylor A O'Brien A Redshaw S Riddell D Rowland P Soleil V Smith KJ Stanway S Stemp G Sweitzer S Theobald P Vesey D Walter DS Ward J Wayne G 《Bioorganic & medicinal chemistry letters》2008,18(3):1017-1021
This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures. 相似文献
19.
Potent, orally active inhibitors of lipoprotein-associated phospholipase A(2): 1-(biphenylmethylamidoalkyl)-pyrimidones. 总被引:4,自引:0,他引:4
Helen F Boyd Stephen C M Fell Deirdre M B Hickey Robert J Ife Colin A Leach Colin H Macphee Kevin J Milliner Ivan L Pinto D Anthony Rawlings Stephen A Smith Ian G Stansfield Steven J Stanway Colin J Theobald Caroline M Whittaker 《Bioorganic & medicinal chemistry letters》2002,12(1):51-55
A series of 1-(biphenylmethylamidoalkyl)-pyrimidones has been designed as nanomolar inhibitors of recombinant lipoprotein-associated phospholipase A(2) with high potency in whole human plasma. 5-(Pyrazolylmethyl) derivative 16 and 5-(methoxypyrimidinylmethyl) derivative 27 demonstrated excellent pharmacodynamic profiles which correlated well with their pharmacokinetic effects. 相似文献
20.
G. W. Theobald 《BMJ (Clinical research ed.)》1959,1(5121):560-561