Chemical optimization

J. Kalivas, Adaption of Simulated Annealing to Chemical Optimization Problems. Elsevier Science, New York, 1995. 

The development of maraviroc (21), much like other chemokine receptor antagonists, started with a high-throughput screen employing a competition binding assay and led to the hit compound UK-107,543. Chemical optimization of this compound led to the development candidate UK-427,857 during this optimization phase, a parallel characterization of the compounds was performed... 

Trubetskoy, V.S., Narula, J., Khaw, B.A., and Torchilin, V.P. (1993) Chemically optimized antimyosin Fab conjugates with chelating polymers Importance of the nature of the protein-polymer single site covalent bond for biodistribution and infarction localization. Bioconjugate Chem. 4, 251-255. 

Drug development is a long and cost-intensive business. Only after years of lead identification, chemical optimization, in vitro and animal testing can the first clinical trials be conducted. Unfortunately, many projects still fail in this late stage of development after a considerable amount of money has been spent. According to estimates, preapproval costs for a new drug exceed US 800 million [1]. 

Guidance of Chemical Optimization to Avoid GPCR-Mediated Side Effects... 

Chemical optimization of affinity of the most active compounds... 

Chemical optimization of the selectivity and specificity of the most potent compounds... 

Chemical optimization of the bioavailability and safety of the most promising compounds. 

The success of this method relies on the hypothesis that the chemical optimization of the molecule for its affinity for one target will not increase its affinity for unwanted targets. There are, however, many examples of discovery programs where hypothesis did not hold. 

While poisonous plants on grazing lands have a significant impact on livestock production throughout the world, the natural toxins (secondary metabolites) in the plant may have multiple and diverse functions, not only for the plant world but also for the benefit of mankind. Many current pharmaceuticals have been chemically optimized from natural toxins of plant origin. New plant compounds and familiar compounds with renewed interest, e.g., nutraceuticals, herbal preparations, nutritional supplements, etc, are increasingly finding their value in human nutrition and health. 

Fig. 14.9 Individual components of multidimensional optimization. This approach requires experimental compound profiling against key properties, which should be done on a designed compound subset to maximize information with a minimum number of molecules. These data are used to derive models for key properties, which are applied during the next design cycle. The results then led to augmented models. The process is characterized by a tight integration of in vitro and in silico tools for profiling compound series to guide chemical optimization.

Chem. Soc., 126, 14411-14418 Skander, M., Malan, C., Ivanova, A. and Ward, TR. (2005) Chemical optimization of artificial metaUoenzymes based on the biotin-avidin technology (S)-selective and solvent-tolerant hydrogenation catalysts via the introduction of chiral amino acid spacers. Chem. Commun., 4815-4817 Ward, TR. (2005) Artificial metallo-enzymes for enantioselective catalysis based on the noncovalent incorporation of organometallic moieties in a host protein. Chem.-Eur. J., 11, 3798-3804 Letondor, C. and Ward, TR. (2006) Artificial metaUoenzymes for enantioselective catalysis Recent advances. Chem. Bio. Chem., 7, 1845-1852. 

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