Small molecule libraries

J.A. Ellman, Design, Synthesis, and Evaluation of Small-Molecule Libraries, Acc Chem. Res 29 132-143 1996. 

Src Homology-2 Domains and Structure-Based, Small-Molecule Library Approaches to Drug Discovery... 

VI. STRUCTURE-BASED, SMALL-MOLECULE LIBRARIES TO EXPLORE Src SH2 BINDING... 

Kaldor SW, Siegel MG, Dressman BA, Hahn PJ (1996) Use of solid supported nucleophiles and electrophiles for the purification of non-peptide small molecule libraries. Tetrahedron Lett 37 7193-7196... 

Keywords Combinatorial Chemistry m Solid-Phase Synthesis m Solid-Phase Scavenger m Linker m Targeted Library m Small Molecule Libraries... 

S. W. Kaldor, M. G. Siegel, J. E. Fritz, B. A. Dressman, P. J. Hahn, Use of Solid Supported Nucleophiles and Electrophiles for the Purification of Non-Peptide Small Molecule Libraries , Tetrahedron Lett. 1996,37,7193-7196. 

Currently, this is a major application of protein crystallography in most of the major drug companies. One of the best examples of this approach is the design of inhibitors for HIV protease (Dash et al., 2003). In brief, once the 3-D structure of HIV protease was determined, the active site was identified and used to screen small molecule libraries for potential compounds that could bind to HIV protease. These compounds were then tested for their ability to inhibit the protease. Lead compounds were then used to iteratively improve the inhibitors, using crystallographic studies, computational modeling, and biochemical tests. 

The introduction of alkoxy groups onto the benzhydryl system leading to a system cleavable by HE was first reported by Walter in 1976 [25] while one additional alkoxy group leads to the Rink linker (12), introduced in 1987 [26]. As quite mild conditions are sufficient for the release of the library components, the Rink resin has effectively been applied to the synthesis of several small molecule libraries [27]. 

A linker originally designed for solid-phase synthesis of peptides is the backbone amide linker (11) (BAL), this anchoring approach has now been extended to the combinatorial synthesis of diverse amide [31], hydroxamate [32], oligosaccharide [33] and heterocyclic small molecule libraries [34-36]. 

Nowadays, solid-phase synthesis has been used as a powerful tool in organic chemistry, especially to prepare small molecule libraries. New linkers to obtain different functionalities after cleavage have been developed. There are different linkers strategies (Fig. 3.2), for example traceless linkers, multifunctional linkers, safety catch linkers, fragmentation/ cycloreversion cleavage linkers, cyclization cleavage linkers, which are useful methods for combinatorial solid-phase chemistry. 

For a review, see (a) Synthesis and Applications of Small Molecule Libraries, L.A. Thompson, J.A. Ellman, Chem. 

Carell, T., Wintner, E.A., Sutherland, A.J., Rebek, J. Jr, Dunayevskiy, Y.M., and VouROS, P. New promise in combinatorial chemistry synthesis, characterization, and screening of small-molecule libraries in solution. Chem. Biol. 1995, 2, 171-183. 

For targets without leads, a lead generation approach is employed if work on such a target is to continue. Such approaches usually require the construction of small-molecule libraries in order to maximize the chances of finding compounds of some level of minimal potency necessary to identify a hona fide lead useful for further optimization. Lead generation library design should emphasize design quality of the individual molecules over their numbers. This topic has been discussed extensively [12]. 

Calculation of ADME predictions is now routine and often high throughput. However, unlike many published studies in which calculated properties are validated with experimental data for a diverse collection of molecules, for virtual small-molecule libraries, there are usually no physical data to validate the predictions. Often, the molecules that are the subject of calculation are dissimilar to those molecules used to develop prediction tools. As a result, one is usually looking for trends in the prediction as a function of the selection of specific diversity reagents around a common core or scaffold. Thus, it is important to consider predicted molecular properties with care and to interpret the results with the proper level of expectation. 

Virtual Screening of Small-molecule Library with Peptide-derived Pharmacophores 421... 

We have developed a high throughput ultrafiltration affinity screening method coupled to MS (affinity selection/mass spectrometry ASMS), which works with any soluble target and small molecule library (including natural products). ASMS is amenable to parallelization, efficient and robust enough to allow study... 

Wieboldt R, Zweigenbaum J, Henion J immunoaffinity ultrafiltration with ion spray HPLC/MS for screening small-molecule libraries. Anal Chem 1997, 69, 1683-1691. 

Scheme 79. The split and combine method of preparing a combinatorial small molecule library...

Goodnow RA, Jr., Cuba W, Haapl W. (2003) Library design practices for success in lead generation with small molecule libraries. Comb. Chem. High Throughput. Screen. 6 649-660. 

Figure 3. Approaches to cluster protein targets for screening of small molecule libraries. Currently, protein targets are clustered based on functional or amino acid sequence similarity (left). We propose to cluster proteins purely based on structural similarity of protein cores and to apply this clustering to compound library design (right).

Oikawa M, Ikoma M, Sasaki M (2005) Parallel synthesis of tandem Ugi/Diels-Alder reaction products on a soluble polymer support directed toward split-pool realization of a small molecule library. Tetrahedron Lett 46 415-418... 

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