Combinatorial Chemistry with Natural Product-Like Libraries

Combinatorial Chemistry with Natural Product-Like Libraries... 

While this may in fact be the case for natural product mixtures, it is rarely the case when dealing with synthesized mixtures. Despite our attempts to create real molecular diversity in the test tube, our efforts have not even begun to anticipate the true diversity of atomic connectivity within "drug space" (estimated to be of the order of 1063 unique compounds, theory, famously in this case, greatly outpacing the amount of matter in the universe). Thus, combinatorial chemistry was never practically able to produce true chemical diversity and compounds produced in such library format ended up looking very much like one another, with the attendant similarities in biological activity profiles. 

Figure 6. Distributions of essential computed molecular properties defining drug-likeness for selected compound sets. Shown are the fraction of compounds vs. the properties. Orange NIBR historical medicinal chemistry collection. Brown Compilation of combinatorial chemistry libraries. Dark Green Drugs (launched or Phase III listed in MDDR or CMC). Brown Compilation from combinatorial libraries. Pink Natural products of DNP. tight Green HTS hits of NIBR 2004 screens. All properties were calculated with Pipeline Pilot software www.scitegic.com).

As noted above, the field of combinatorial chemistry and multiple parallel synthesis started with libraries of peptides. In time, unusual residues crept into the products. While this evolutionis still ongoing, it is now accompanied by a major effort to produce libraries of small, drug-like molecules in library form. Many of the methods used for large molecules carry over but the largely non-iterative nature of small molecule synthesis is a significant complication. 

As a source of novel chemical structures, natural products are now rivaled by the revolution that is combinatorial chemistry by which a vast number of compounds may be made from a relatively small number of starting compounds, or monomers (87). An alliance of natural products chemistry with combinatorial chemistry has resulted m the development of several libraries of natural product derivatives, using natural products as templates (88) and as targets for total synthesis on solid phase (89). Whereas natural products have often been the target or the starting point for synthetic chemists, the use of natural products as combinatorial chemistry monomers is likely to increase enormously the numbers of natural product-denved structures available for testing. 

As sampling of chemical space will be even more sparse with increasing size of the molecules, it may be required to revert to other technologies like fragment-based screen, natural products, DNA-encoded libraries, or dynamic combinatorial chemistry to generate starting points for lead identification. 

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