Characterization of Sar

Wawer M, Sun S, Bajorath J. Computational characterization of SAR microenvironments in high-throughput screening data. Int J High Throughput Screen 2010 1 15-27. 

Lee TW, Chemey MM, Huitema C, Liu J, James KE, Powers JC, Eltis LD, James MN (2005) Crystal structures of the main peptidase from the SARS coronavirus inhibited by a substrate-fike aza-peptide epoxide. J Mol Biol 353 1137-1151 Liang PH (2006) Characterization and inhibition of SARS-coronavirus main protease. Curr Top Med Chem 6 361-376... 

In summary, based on the observation of divergent in vitro and in vivo SAR, a new class of cholesterol-lowering compounds was discovered. Subsequent biological characterization of the first generation lead compound SCH-48461, limited the site of action to be at or near the intestinal villi, with the most probable mechanism being the inhibition of luminal absorption. An SAR optimization based solely on an in vivo assay and without biochemical characterization of the molecular target led to the design of ezetimibe (1). 

The fourth and fifth chapters review the efforts and achievements made in the characterization of the structure of the complexes of tubulin with microtubules stabilizing agents by NMR (Chapter 4) and EM (Chapter 5). Especially evident is the discrepancy of the results obtained for epothilones, where the two techniques deliver radically different structures of the bound drug. Both NMR and EM models are, however, able to explain a consistent set of SAR data. The authors of the two chapters discuss critically the advantages and limitations of each methodology. 

M.H. Chisholm, J.F. Coming, J.C. Huffman, The molybdenum-molybdenum triple bond. 14. Preparation and characterization of mixed alkoxy-thiolate compounds of formula Mo2(OR)2(SAr)4. Inorg. Chem. 23, 754-757 (1984)... 

Visualization of landscapes via network diagrams has also led to novel developments in the exploration of SAR data. Examples include the SALI networks described by Guha and Van Drie (38) and network similarity graphs (NSGs) described by Wawer et al. (40). Both network representations use compounds as nodes and draw edges between them based on a metric that characterizes the pair of nodes in the context of the landscape (SARI for NSGs and SALI for SALI networks). The networks can be then analyzed to identify specific SAR trends. For example, Wawer et al. (41) described an approach to identifying SAR pathways (paths in an... 

All the spectroscopic approaches applied for structural characterization of mixtures derive from methods originally developed for screening libraries for their biological activities. They include diffusion-ordered spectroscopy [15-18], relaxation-edited spectroscopy [19], isotope-filtered affinity NMR [20] and SAR-by-NMR [21]. These applications will be discussed in the last part of this chapter. As usually most of the components show very similar molecular weight, their spectroscopic parameters, such as relaxation rates or selfdiffusion coefficients, are not very different and application of these methodologies for chemical characterization is not straightforward. An exception is diffusion-edited spectroscopy, which can be a feasible way to analyze the structure of compounds within a mixture without the need of prior separation. This was the case for the analysis of a mixture of five esters (propyl acetate, butyl acetate, ethyl butyrate, isopropyl butyrate and butyl levulinate) [18]. By the combined use of diffusion-edited NMR and 2-D NMR methods such as Total Correlation Spectroscopy (TOCSY), it was possible to elucidate the structure of the components of this mixture. This strategy was called diffusion encoded spectroscopy DECODES. Another example of combination between diffusion-edited spectroscopy and traditional 2-D NMR experiment is the DOSY-NOESY experiment [22]. The use of these experiments have proven to be useful in the identification of compounds from small split and mix synthetic pools. 

In addition to extending the utility of analytical NMR, these developments have had a direct impact on screening methodologies, where NMR spectroscopy may now be used directly as a rapid and sensitive method for the characterization of binding affinities of mixtures of compounds in combinatorial libraries.3,9 11 A powerful screening method based on observation of NMR signals from a protein target has been developed by researchers at Abbott laboratories.12 Termed SAR (structure-activity relationship) by NMR, this technique has proved to be extremely valuable for the identification of novel lead compounds. 

Refs. [i] Horanyi G (1999) Radiotracer studies of adsorption/sorption phenomena at electrode surfaces. In Wieckowski A(ed) Interfacial electrochemistry, theory, experiment, and applications. Marcel Dekker, New York, pp 477-491 [ii] Kalman E, Lakatos M, Karman FH, Nagy F, Klenc-sar Z, Virtes A (2005) Mossbauer spectroscopy for characterization of corrosion products and electrochemically formed layers. In Freund HE, Zewi I (eds) Corrosion reviews. Freund Publishing House, Tel Aviv, pp 1-106 [iii] Horanyi G, Kalman E (2005) Recent developments in the application of radiotracer methods in corrosion studies. In Marcus PH, Mansfeld F (eds) Analytical methods in corrosion science and engineering, CRC Press, Boca Raton, pp 283-333 [iv] Stivegh K, Horanyi TS, Vdrtes A (1988) Electrochim Acta 33 1061... 

Medicinal chemistry has evolved from the chemistry of bioactive compounds in early days to works at the interface of chemistry and biology nowadays. Medicinal chemistry of bioactive natural products spans a wide range of fields, including isolation and characterization of bioactive compounds from natural sources, stmcture modification for optimization of their activity and other physical properties, and total and semi-synthesis for a thorough scmtiny of stmcture activity relationship (SAR). In addition, synthesis of natural products also provides a powerful means in solving supply problems in clinical trails and marketing of the dmg, for obtaining natural products in bulk amounts is often very difficult. 

Basak, S.C. and Gute, B.D. (1997b). Characterization of Molecular Structures Using Topological Indices. SAR QSAR Environ.Res., 7,1-21. 

Nakazato, A., Kumagai, T., Sakagami, K., et al. (2000) Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonist. Journal of Medicinal Chemistry, 43, 4893-4909. 

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