Bioisostere drug discovery

If bond breaking occurs during the rate-determining step of the reaction, then the overall reaction will be slowed by the replacement of hydrogen with deuterium. This is an example of a kinetic isotope effect. The use of deuterium as a bioisostere to manipulate rates of metabolism is a fairly new idea in drug discovery. If SD-254 successfully reaches the market, additional deuterated drugs will almost certainly be advanced into clinical trials. 

In this section we describe some exotic applications of the bioisostery concept implying the utilization of unusual elements such as silicon, boron, selenium, arsenic, and antimony. The use of those elements as bioisosteres of carbon in existing drugs is a different approach enabling the introduction of a new drug-like chemical space into the drug discovery and development process. 

Figure 8.8 Classical and non-classical bioisosteres (Reprinted with permission from, Showell, G.A., Mills, J.S. Chemistry challenges in lead optimization Silicon isosteres in drug discovery. Drug Discov. Today, 8, 551-556, copyright 2003, Elsevier.)...

A set of over 2200 bioisosteric functional groups, linkers, and core scaffolds was extracted from Bioster 2001.1 and used in an unbiased validation of the fragment database of the IBIS drug discovery software [20]. 

Erd, P. (2007) In silico identification of bioisosteric functional groups. Current Opinion in Drug Discovery and Development, 10, 281-288. 

The design and application of bioisosteres in drug discovery has been and will continue to be an important approach to structural modification as medicinal chemists address the wide range of problems that are encountered in contemporary lead optimization initiatives. 

This book concludes with two case studies of where bioisosteric replacement strategies have been applied in drug discovery, to provide demonstrable evidence of their utility. Finally, a few leading scientists in this field have kindly provided personal perspectives on bioisosterism and its relevance to drug discovery. 

Voile J-N, Filippini D, Krawczy B, Kaloyanov N, Van der Lee A, Maurice T, Pirat J-L, Virieux D. Drug discovery phosphinolactone, in vivo bioisostere of the lactol group. Org. Biomol. Chem. 2010 8 1438-1444. 

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