Combinatorial chemistry approach

CHIRSOURCE aims to explore the use of chiral chromatography for combinatorial chemistry approaches. Combinatorial chemistry, as well as parallel synthesis. 

Virtual screening on a 2-D basis is far more efficient in terms of computing time, although the information content of the resulting virtual hits is far less sophisticated than for a 3-D pharmacophore search. It is in this setting that combinatorial chemistry approaches are applied most effectively. The many interactions possible with a compound library based on virtual hits compensates for the inherent fuzziness of any prediction tool. Examples have been described where the 2-D structure of a... 

S., WaUing, T., Wild, H. (2001) Discovery of heterocyclic ureas as a new class of raf kinase inhibitors identification of a second generation lead by a combinatorial chemistry approach. Bioorg Med Chem Lett 11, 2775-2778. 

For an alternative combinatorial approach employing catalytic metal centers bearing two bidentate ligands see Ding, K., Du, H., Yuan, Y. and Long, J. (2004) Combinatorial chemistry approach to chiral catalyst... 

Synthetic combinatorial chemistry approaches have created a vast new source of molecular diversity for the potential identification of lead compounds. This revolutionary field enables hundreds to thousands of times more compounds to be synthesized and screened in shorter periods of time relative to traditional approaches. In particular, novel antibacterials and/or antifungals as well as inhibitory peptides of either HIV proteases or HIV integrase proteins13 were identified following the screening of synthetic combinatorial libraries (SCLs). As described below, SCLs have been used by this laboratory to develop antimicrobial and antifungal compounds, as well as novel treatments for HIV infection. 

One other problem is combinatorially large search spaces. There are 100 million potential candidates for rubber components formulation that are possible. Some other examples we have worked at Purdue have involved 1020 to 1030 different molecules. Another issue is that typically there are limited and uncertain data. Most often, combinatorial chemistry approaches do not succeed in these cases because obtaining the results is time and labor intensive. Fuel additives design, for example, requires dismantling the engine for every test of a new formula. 

The number of individual reactions of a given reaction type that are currently performed and analyzed in parallel combinatorial chemistry approaches is much higher than in the past. Not surprisingly we often observe that some of the expected reaction products in a compound library are not formed since, for various reasons, the corresponding starting materials may not yield the desired product under the chosen reactions conditions. In other cases unexpected reaction products may be formed. 

Distinguish between different combinatorial chemistry approaches... 

Smith, R. A., Barbosa, J., Blum, C. L., Bobko, M. A., Caringal, Y. V., Dally, R., et al. Discovery of Heterocyclic Ureas as a New Class of Raf Kinase Inhibitors Identification of a Second Generation Lead by a Combinatorial Chemistry Approach. Bioorg. Med. Chem. Lett. 2001,11, 2775-2778. 

Cong, P., Giaquinta, D., Guan, S., McFarland, E., Self, K., Turner, H., Weinberg, H., A combinatorial chemistry approach to oxidation catalyst discovery and optimization, in Ehrfeld, W., Rinard, I. H., Wegeng, R. S. (Eds.), Process Miniaturization 2nd International Conference on Microreaction Technology, IMRET 2, Topical Conf. Preprints, AIChE, New Orleans, 1998, 118-123. 

A more random approach to discovering a lead is the combinatorial chemistry approach (see Chapter 6). This uses a simultaneous multiple synthesis technique to produce large numbers of potential leads. These potential leads are subjected to rapid high throughput biological screening to identify the most active lead compounds. Once identified, these lead compounds are subject to further development. 

Xeptagen S.p.A. has improved a computer assisted combinatorial chemistry approach, based on an innovative application of Mitsunobu reaction, that could be used to design and synthesize new peptido-mimetic libraries, in order to find novel leads efficient in different biological targets (Figure 3.10). 

We should stress that modern combinatorial chemistry approaches span a chemistry space that easily contains 1060 drug-like molecules [6]. No computational... 

In this section we consider several examples of virtual screening performed on a database containing only virtual (still non-synthesized or unavailable) compounds. Virtual libraries are usually generated using combinatorial chemistry approaches. One of simplest ways is to attach systematically user-defined substituents R, R2,. . . , Rn to a given scaffold. If the list for the substituent R,-contains candidates, the total number of generated structures is ... 

The poor discovery rate for new leads from combinatorial chemistry approaches indicate that natural products chemistry will continue to warrant support. However attention to source material, particularly the true biological origin of desired metabolites, direct assessments of chemical diversity and effective dereplication strategies, is essential. 

Recent strategies in CSP development and optimization related to the Pirkle concept and to low molecular weight synthetic chiral selectors. In the attempt to proceed more effectively with the development of new tailor-made CSPs, solid-phase syntheses and combinatorial chemistry approaches involving SO and/or CSP libraries have been tested. 

Fig. 9.28. SO libraries with cyclic structure and consisting of three chiral modules prepared by a combinatorial chemistry approach and implementing a atlour-coded screening assay (reprinted with permission from Ref. 1.172]).

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