Combinatorial chemistry defined

Thorpe, D. S. and Walle, S. (2000) Combinatorial chemistry defines general properties of Hnkers for the optimal display of peptide ligands for binding soluble protein targets to tentagel microscopic beads. Biochem. Biophys. Res. Commun. 269,591-595. 

Precisely defined collections of different chemical compounds are denominated as chemical libraries that can be efficiently prepared by methods of combinatorial chemistry. Each chemical compound owes specific structural, steiic, and electronic properties that determine all possible interactions of the small molecule with a given protein or receptor. The molecule s properties are based on the steiic arrangement of functional groups, including the conformations that can be attained by a specific structure. 

Parallel processing of synthetic operations has been one of the cornerstones in combinatorial chemistry for years [1-6]. In the parallel synthesis of combinatorial libraries, compounds are synthesized using ordered arrays of spatially separated reaction vessels adhering to the traditional one vessel-one compound philosophy. The defined location of the compound in the array provides the structure of the compound. A commonly used format for parallel synthesis is the 96-well microtiter plate, and today combinatorial libraries comprising hundreds to thousands of compounds can be synthesized by parallel synthesis, often in an automated fashion [6]. 

Combinatorial chemistry was developed in the early 1990s with pharmaceutical industry being the main driver [3], The rapid screening of potential drug molecules against well-defined assays had quickly become one of the major tools for the identification of novel lead candidates. 

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).

Another recent development in pharmaceuticals is combinatorial chemistry. This term is difficult to define, but generally it means the high-throughput synthesis and screening of chemical substances to identify agents with useful properties. Making small amounts of many slightly different... 

Combinatorial chemistry is both the philosophical and the practical method with which to create structurally diverse compound libraries. Combinatorial chemistry is defined as that branch of synthetic organic chemistry that enables the concomitant synthesis of large numbers of chemical variants in such a manner as to permit their evaluation, isolation, and identification. Combinatorial chemistry affords techniques for the systematic creation of large but structurally diverse libraries. From a technical perspective, there are several avenues of approach to library creation ... 

High-throughput synthesis and combinatorial chemistry employing polymer supports, with computer-based rational design, are important tools for systematic optimization of the affinity, selectivity, and bio-availability of protease inhibitors. It is very likely that currently available isosteres will not suffice for addressing the natural selectivity of proteases. Thus, synthetic methodology must be devised not only to decorate a predefined isosteric core but to define novel active site binders. 

There are basically three types of patent claims (i) product or compound claims (ii) process or method claims and (iii) product-by-process claims (see Table 3). The name of each type of claim is self-defining. Product claims cover devices such as robotics [2] which are used in combinatorial chemistry. In addition, these claims can cover a particular compound, group of compounds or even an entire library of compounds [3], Note that... 

Combinatorial chemistry has an unusual patent history. No single company or individual has control of any one strategic patent and there is no single strategic patent that defines the field. Many companies have patents that enable them to pursue unique chemistries, and this provides investors with many choices. On the other side, exclusivity is reduced. 

Any combinatorial chemistry campaign or design strategy should be geared to finding leads quickly, and furthermore should enable those hit compounds to be turned into a lead series. Ecker and Crooke proposed criteria that define value as regards combinatorial chemistry and diversity analysis [6] ... 

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