Fragment-Based Drug Design

다국어 초록 (Multilingual Abstract)

Despite numerous new technologies developed until recent years, lead discovery remains a high-risk endeavor. Combinatorial chemistry technology(combichem) and high throughput screening(HTS) have tremendously increased throughputs of chemical synthesis and screening. Although a vast investment from major pharmaceutical companies in these new technologies have shown successes in many targets, the number of NCEs entering development has not increased accordingly. Now it is believed that what is more important is the quality of leads rather than the number, in order to increase a success rate in clinical development. One of the new methods for lead generation is fragment-based discovery, in which low molecular weight molecules(fragments) are identified by NMR, X-ray, or possibly molecular modeling and these fragments are converted into potential drug leads by evolution, linking, or self-assembly. High throughput methods in the fragment-based screening include "SAR by NMR" pioneered by Fesik et al and "HTX", high throughput X-ray crystallography adopted by Astex Technology. Low molecular weight molecules identified by fragment-based screening generally have a lower potency than HTS hits. Once fragment hits are confirmed to bind the target protein, molecular modeling methods such as de novo design may be employed to link two or more fragment hits or to grow into more complex molecules in order to increase efficacy. This talk will cover the fragment-based drug discovery approach with some case studies.