Combinatorial biotechnology

Ostermeier, M., Shim, J.H. and Benkovic, S.J. (1999) A combinatorial approach to hybrid enzymes independent of DNA homology. Nature Biotechnology, 17, 1205-1209. 

Boder, E.T. and Wittrup, K.D. (1997) Yeast surface display for screening combinatorial polypeptide libraries. Nature Biotechnology, 15, 553-557. 

Khosla, C. (1996) Combinatorial chemistry and biology an opportunity for engineers. Current Opinion in Biotechnology, 7, 219. 

Khosla, C.Z.R. (1996) Generation of polyketide libraries via combinatorial biosynthesis. Trends in Biotechnology, 14, 335-341. 

Menzella, H.G., Reid, R., Carney, J.R. et al. (2005) Combinatorial polyketide biosynthesis by de novo design and rearrangement of modular polyketide synthase genes. Nature Biotechnology, 23, 1171-1176. 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

Although, MediChem is a biosecurity products manufacturer, its biotechnology-based R D capabilities are worth mentioning here. The attended markets include Medical, Laboratory, Veterinary, and Environmental sectors. Medicinal chemistry services and drug discovery form the basis of the company, though their capabilities might be applied in a broader range of sectors. These capabilities comprise the areas of Proteomics, Combinatorial and Computational Chemistry, Medicinal Chemistry, Enzymes, Process Development, Analytical and Separations Chemistry, Chemical Synthesis and Scale Up. 

With the advent of computer-aided-drug modeling (CADM) the critical, scientific and faster approach to newer drug entities based on the biologically active prototypes, combinatorial chemistry, chiral chemistry and biotechnology has paved the way towards more specific, potent and above all less toxic drugs to improve the ultimate quality of life in humans. 

Advances in biotechnology have been tremendous. There are many issues in biochemistry and biotechnology that have not yet been completely elucidated however, progress has been made. For example, antibiotics have evolved, the polymerase chain reaction has been developed, and DNA sequencing, genomics, proteomics, combinatorial synthesis, and selective complexation and recognition chemistry have all advanced. 

The availability of ctetq) advanced synthons that carry the required chirality is an advantage, particularly in projects aimed at industrial total synthesis. Natural products are often used as synthons, ideally fi om a renewable source, such as microbial fermentations. In a few cases, biotechnology has become an ahemative source. The total theses of the antitumor agent esperamicin A and the immunosuppressant FK-506 are exanq>les. In both cases, the synthon was quinic acid (Barco 1997), cheaply obtained by biotechnology (Chapter 14.1.e) rather than fi om the environmentally noxious extraction fi om the bark of Cinchona spp. Used to build up combinatorial libraries, quinic acid has gained further inq)ortance in organic thesis (Phoon 1999). 

Target enzymes expressed biotechnologically are also introduced to HTS systems. Merck researchers reported a new approach to drug screening by combinatorial enzymology [121], They have engineered a cell-free bacterial cell wall... 

Other applications are toxicity monitoring and cytotoxin response measurement of cancer cells [104]. Future applications may be strain prescreening in biotechnology, rapid sterility tests and preanalytical screening in combinatorial chemistry. 

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