Combinatorial methods

Combinatorial. Combinatorial methods express the synthesis problem as a traditional optimization problem which can only be solved using powerful techniques that have been known for some time. These may use total network cost direcdy as an objective function but do not exploit the special characteristics of heat-exchange networks in obtaining a solution. Much of the early work in heat-exchange network synthesis was based on exhaustive search or combinatorial development of networks. This work has not proven useful because for only a typical ten-process-stream example problem the alternative sets of feasible matches are cal.55 x 10 without stream spHtting. 

Combinatorial methods are often referred to as in vitro or directed evolution techniques. In nature, the random DNA mutations that lead to changes in protein sequences occur rarely and so evolution is usually a slow... 

EMPl, selected by phage display from random peptide libraries, demonstrates that a dimer of a 20-residue peptide can mimic the function of a monomeric 166-residue protein. In contrast to the minimized Z domain, this selected peptide shares neither the sequence nor the structure of the natural hormone. Thus, there can be a number of ways to solve a molecular recognition problem, and combinatorial methods such as phage display allow us to sort through a multitude of structural scaffolds to discover novel solutions. 

Protein engineering is now routinely used to modify protein molecules either via site-directed mutagenesis or by combinatorial methods. Factors that are Important for the stability of proteins have been studied, such as stabilization of a helices and reducing the number of conformations in the unfolded state. Combinatorial methods produce a large number of random mutants from which those with the desired properties are selected in vitro using phage display. Specific enzyme inhibitors, increased enzymatic activity and agonists of receptor molecules are examples of successful use of this method. 

Ultramodern techniques are being applied to the study of corrosion thus a very recent initiative at Sandia Laboratories in America studied the corrosion of copper in air spiked with hydrogen sulphide by a form of combinatorial test, in which a protective coat of copper oxide was varied in thickness, and in parallel, the density of defects in the copper provoked by irradiation was also varied. Defects proved to be more influential than the thickness of the protective layer. This conclusion is valuable in preventing corrosion of copper conductors in advanced microcircuits. This set of experiments is typical of modern materials science, in that quite diverse themes... combinatorial methods, corrosion kinetics and irradiation damage... are simultaneously exploited. 

Chiral separation media are quite complex systems. Therefore, neither combinatorial methods nor even the identification of the best selector can ensure that an outstanding chiral separation medium will be prepared. This is because some other variables of the system such as the support, spacer, and the chemistry used for their con-... 

These conceptual goals are attained by several combinatorial methods and tools. Characteristic for combinatorial chemistry is the synthesis on solid support or by polymer-supported synthesis, allowing for much higher efficiency in library production. Synthesis can be conducted either in automated parallel synthesis or by split-and-recombine synthesis. Centerpieces of combinatorial methods further include specific analytical methods for combinatorial... 

Introduced in the early 1990s, the split-and-recombine concept contributed much to the early success of combinatorial chemistry. Often, all combinatorial methods were identified with this concept. Split-and-recombine synthesis offered easy access to large number of individual compounds in few steps. If conducted on polymer beads, these are easily separated mechanically and can be identified subsequent to a screening step. 

Essential prerequisites for the evolution of combinatorial methods were the progress in reaction monitoring and analytics. Of specific importance was the analytics... 

Since drug development has turned into a systematic and rational task of optimizing molecules and their interactions with proteins, cells, and organisms, combinatorial chemistry has become a significant part of this endeavor. Combinatorial methods are mainly employed in the initial (preclinical) stages of drug development. 

Zech, T, Honicke, D., E ient ond reliable screening of catalysts for microchannel reactors by combinatorial methods, in Proceedings of the 4th International Conference on Microreaction Technology, IMRET 4, pp. 379-389 (5-9 March 2000), AIChE Topical Conf Proc., Atlanta, USA. 

Weber, L., Illgen, K., Almstetter, M. (1999) Discovery of New Multi-Component Reactions with Combinatorial Methods. Synlett, 366-374. 

Hagemeyer A, Jandeleit B, Liu YM, Poojary DM, Turner HW, Volpe AF, Weinberg WH. 2001. Applications of combinatorial methods in catalysis. Appl Catal A Gen 221 23-43. 

The objective of traditional multistep synthesis is the preparation of a single pure compound, but combinatorial synthesis is designed to make many related molecules.57 The purpose is often to have a large collection (library) of compounds for evaluation of biological activity. A goal of combinatorial synthesis is structural diversity, that is, systematic variation in subunits and substituents so as to explore the effect of a range of structural entities. In this section, we consider examples of the application of combinatorial methods to several kinds of compounds. 

The popular permeability equations [(7.10) and (7.11)] derived in the preceding section presume that the solute does not distribute into the membrane to any appreciable extent. This assumption may not be valid in drug discovery research, since most of the compounds synthesized by combinatorial methods are very lipophilic and can substantially accumulate in the membrane. Neglecting this leads to underestimates of permeability coefficients. This section expands the equations to include membrane retention. 

Hoogenboom, R., Meier, M.A.R. and Schubert, U.S. (2003) Combinatorial methods, automated synthesis and high-throughput screening in polymer research past and present. Macro-mol. Rapid Commun., 24, 16. 

Serra, J.M., Chica, A. and Corma, A. (2003) Development of a low temperature light paraffin isomerization catalysts with improved resistance to water and sulphur by combinatorial methods. Appl. Catal. A Gen., 239, 35. 

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