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101.
Single crystal X-ray diffraction is the technique of choice for studying the interactions of small organic molecules with proteins by determining their three-dimensional structures; however the requirement for highly purified protein and lack of process automation have traditionally limited its use in this field. Despite these shortcomings, the use of crystal structures of therapeutically relevant drug targets in pharmaceutical research has increased significantly over the last decade. The application of structure-based drug design has resulted in several marketed drugs and is now an established discipline in most pharmaceutical companies. Furthermore, the recently published full genome sequences of Homo sapiens and a number of micro-organisms have provided a plethora of new potential drug targets that could be utilised in structure-based drug design programs. In order to take maximum advantage of this explosion of information, techniques have been developed to automate and speed up the various procedures required to obtain protein crystals of suitable quality, to collect and process the raw X-ray diffraction data into usable structural information, and to use three-dimensional protein structure as a basis for drug discovery and lead optimisation.This tutorial review covers the various technologies involved in the process pipeline for high-throughput protein crystallography as it is currently being applied to drug discovery. It is aimed at synthetic and computational chemists, as well as structural biologists, in both academia and industry, who are interested in structure-based drug design. 相似文献
102.
[reaction: see text] Glucuronyl iodide 1 has been studied in detail as a "disarmed" glycosyl donor. In a model reaction, using N-iodosuccinimide (NIS) as a promoter and 2-phenylethanol as acceptor, best results were obtained using NIS with I(2), followed by trimethylsilyltrifluoromethanesulfonate (TMSOTf). When a series of primary and secondary alcohols was glycosylated using these conditions, yields of 60-83% of beta-glucuronides were obtained. Various "nonheavy" metal salts also effectively catalyzed the model reaction but led to significant amounts of alpha-product with less reactive secondary alcohols. 相似文献
103.
Beevers AP Fettes KJ Sabbagh G Murad FK Arnold JR Cosstick R Fisher J 《Organic & biomolecular chemistry》2004,2(1):114-119
High-resolution NMR spectroscopy has been used to establish the conformational consequences of the introduction of a single 3[prime or minute]-S-phosphorothiolate link in the DNA strand of a DNA : RNA hybrid. These systems are of interest as potential antisense therapeutic agents. Previous studies on similarly modified dinucleotides have shown that the conformation of the sugar to which the sulfur is attached shifts to the north (C(3[prime or minute])-endo/C(2[prime or minute])-exo). Comparisons made between NOESY cross-peak intensities, and coupling constants from PE-COSY spectra, for both non-modified and modified duplexes confirm that this conformational shift is also present in the double helical oligonucleotide system. In addition it is noted that in both the dinucleotides and the modified duplex, the conformation of the sugar ring 3[prime or minute] to the site of modification is also shifted to the north. That this pattern is observed in the small monomeric system as well as the larger double helix is suggestive of some pre-ordering of the sequences. The conclusion is supported by consideration of the (1)H chemical shifts of the heterocyclic bases near the site of the modification. The enhanced stability that these conformational changes should bring was confirmed by UV thermal melting studies. Subsequently a series of singly and doubly 3[prime or minute]-S-phosphorothiolate-modified duplexes were investigated by UV. The results are indicative of an additive effect of the modification with thermodynamic benefit being derived from alternate spacing of two modified linkers. 相似文献
104.
Ogrin D van Poppel LH Bott SG Barron AR 《Dalton transactions (Cambridge, England : 2003)》2004,(21):3689-3694
The reaction of AlMe(3) and [((t)Bu)(2)Al(micro-OPh)](2) with pyrazine (pyz), 4,4'-bipyridine (4-4'-bipy), 1,2-bis(4-pyridyl)ethane (bpetha) and 1,2-bis(4-pyridyl)ethylene (bpethe) yields (Me(3)Al)(2)(micro-pyz)(1), (Me(3)Al)(2)(micro-4,4'-bipy)(2), (Me(3)Al)(2)(micro-bpetha)(3), (Me(3)Al)(2)(micro-bipethe)(4), Al((t)Bu)(2)(OPh)(pyz)(5), [((t)Bu)(2)Al(OPh)](2)(micro-4,4-bipy)(6a), [((t)Bu)(2)Al(OPh)](2)(micro-bpetha)(7a), [((t)Bu)(2)Al(OPh)](2)(micro-bipethe)(8a). Compounds 1-4, 6a and 7a have been confirmed by X-ray crystallography. In solution compounds 1-4 undergo a rapid ligand-dissociation equilibrium resulting in a time-average spectrum in the (1)H NMR. In contrast, the solution equilibria for compounds 5-8a are sufficiently slow such that the mono-aluminium compounds may be observed by (1)H NMR spectroscopy: Al((t)Bu)(2)(OPh)(4,4-bipy)(6b), Al((t)Bu)(2)(OPh)(bpetha)(7b) and Al((t)Bu)(2)(OPh)(bpethe)(8b). The inability to isolate [((t)Bu)(2)Al(OPh)](2)(micro-pyz) and the relative stability of each complex is discussed with respect to the steric interactions across the bridging ligand (L) and the electronic effect on one Lewis acid-base interaction by the second Lewis acid-base interaction on the same ligand. 相似文献
105.
Horvath JD Koritnik A Kamakoti P Sholl DS Gellman AJ 《Journal of the American Chemical Society》2004,126(45):14988-14994
Kinked-stepped, high Miller index surfaces of metal crystals are chiral and, therefore, exhibit enantiospecific properties. Previous temperature-programmed desorption (TPD) spectra have shown that the desorption energies of R-3-methylcyclohexanone (R-3-MCHO) on the chiral Cu(643)(R) and Cu(643)(S) surfaces are enantiospecific (J. Am. Chem. Soc. 2002, 124, 2384). Here, a comparison of the TPD spectra from Cu(111), Cu(221), Cu(533), Cu(653)(R&S), and Cu(643)(R&S) surfaces reveals that the enantiospecific desorption occurs from the chiral kink sites on the Cu(643) surfaces. Titration of the chiral kink sites with I atoms confirms this assignment of desorption features in the TPD spectra. Finally, the enantiospecific difference in the desorption energies of R- and S-3-MCHO has been used as the basis for demonstration of an enantioselective, kinetic separation of racemic 3-MCHO into its purified components during adsorption and desorption on the Cu(643)(R&S) surfaces. 相似文献
106.
Journal of Theoretical Probability - Let $$ \{X, X_{n};~n \ge 1 \}$$ be a sequence of independent and identically distributed Banach space valued random variables. This paper is devoted to... 相似文献
107.
Ying-Sing Fung Andrew Shin-Kwan Tang 《Fresenius' Journal of Analytical Chemistry》1994,350(12):721-723
A fast, simple and reliable method for the analysis of DEHP in PVC products was developed using a one-step Soxhlet extraction prior to HPLC determination. The linear range from 1.25 /g to 250 mg/g of DEHP in PVC was found sufficient to cover the normal concentrations encountered. The reliability of the method was established by comparison with the ASTM method and no potential interferent was identified except a large concentration of DIMP. 相似文献
108.
Elliptic genera of level N have been defined by F. Hirzebruch,generalising the earlier notion of elliptic genus due to S.Ochanine. We show that there are corresponding elliptic cohomologytheories which are naturally associated to such genera and thatthese are obtained from the level 1 case by algebraic extensionof the coefficient rings from level 1 to level N modular forms. 相似文献
109.
110.
The pentacyclic marine alkaloids (-)-papuamine (1) and (-)-haliclonadiamine (2) have been prepared by total synthesis. The synthesis began with (-)-8, which was converted into diester 20 by way of bis-mesylate 17, dinitrile 18, and diacid 19. Dieckmann cyclization of 20 provided keto ester 21, which was transformed into acetal 22. After hydrolysis of the acetal, ketone 25 was subjected to reductive amination with 1,3-propanediamine and sodium triacetoxyborohydride to obtain diamines 26 and 27 as a 71:29 mixture of diastereomers, favoring the symmetrical isomer having the papuamine relative configuration. After transformation of the diamines to their t-Boc derivatives, the benzyl ethers were cleaved and the resulting diol was oxidized to dialdehyde 30. Application of the Seyferth procedure for conversion of aldehydes to alkynes gave a mixture of diynes 31 and 32. After removal of the t-Boc protecting groups from 31, diamino diyne 15 was treated with tributylstannane and azoisobutyronitrile to obtain the bis-vinylstannane 34. Treatment of this compound with Pd(II) and Cu(I) in the presence of air produced (-)-papuamine (1). (-)-Haliclonadiamine (2) was obtained from the unsymmetrical isomer, 32. The NMR spectra of the synthetic alkaloids were identical to those of authentic samples of the natural alkaloids. 相似文献