Fragment-based drug discovery: opportunities for organic synthesis

Abstract

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.

Fig. 1. Example of a protein–fragment crystal structure that is used to identify specific growth vectors (arrows) to guide fragment-to-lead elaboration.

Fig. 2. Representative examples of common functional groups added during fragment elaboration. Note – not an exhaustive list of functional groups. HAC = number of non-hydrogen atoms (heavy atom count).

Fig. 3. Urokinase-type plasminogen activator (uPA)-fragment co-complexes A) overlay of unsociable fragment 1 (orange) and sociable fragment 2 (green) bound to the active site of uPA. B) Overlay of sociable fragment 2 (green) and lead compound 7 (pink). C) Properties and biochemical potencies of unsociable fragment 1, sociable fragment 2, and lead compound 7. Red circle – binding pharmacophore, blue circle and arrow – growth vector.

Fig. 4. Hematopoietic prostaglandin D2-synthase (H-PGDS)-fragment co-complexes A) overlay of unsociable fragment 3 (orange) and sociable fragment 4 (green). B) Overlay of sociable fragment 3 (green) and lead compound 8 (pink). C) Properties and biochemical potencies of fragments 3, 4 and the lead compound 8. Red circle – binding pharmacophore, blue circle and arrow – growth vector.

Fig. 5. Hepatitis C virus NS3 protease-helicase (HCV NS3 protease-helicase) – fragment co-complexes A) overlay of unsociable fragment 5 (orange) and sociable fragment 6 (green). B) Overlay of sociable fragment 6 (green) and lead compound 9 (pink). C) Properties and biochemical potencies of fragments 5, and 6 and the lead compound 9. Red circle – binding pharmacophore, blue circle and arrow – growth vector.

Scheme 1. 12 fragments contained within our fragment library are considered unsociable fragments. These are examples of fragments that require organic methodology development to become sociable.

Scheme 2. Examples of apparently unsociable fragments and the single bond transformation that yields functionalised sociable reagents that enable rapid analogue synthesis via robust organic methods.

Scheme 3. Example of false positive ‘unsociable fragment’ based on functional group manipulation. Simplification of fragment 10 results in a more sociable compound 11 that is growth vector enabled at each carbon atom (selected commercially available examples identified by the fragment network).

Jeffrey D. St. Denis

Richard Hall

Christopher Murray

Tom Heightman

David Rees