Fragment-based drug discovery: opportunities for organic synthesis

This Review describes the increasing demand for organic synthesis to facilitate fragment-based drug discovery (FBDD), focusing on polar, unprotected fragments. In FBDD, X-ray crystal structures are used to design target molecules for synthesis with new groups added onto a fragment via specific growth vectors. This requires challenging synthesis which slows down drug discovery, and some fragments are not progressed into optimisation due to synthetic intractability. We have evaluated the output from Astex's fragment screenings for a number of programs, including urokinase-type plasminogen activator, hematopoietic prostaglandin D2 synthase, and hepatitis C virus NS3 protease-helicase, and identified fragments that were not elaborated due, in part, to a lack of commercially available analogues and/or suitable synthetic methodology. This represents an opportunity for the development of new synthetic research to enable rapid access to novel chemical space and fragment optimisation.

Automated summary

This review discusses the growing demand for organic synthesis in facilitating fragment-based drug discovery, particularly focusing on polar unprotected fragments. It highlights the challenge of synthesis that slows down drug discovery process, and some fragments cannot be further optimized due to synthetic difficulties.