Title:Perspectives on Fragment-based Drug Discovery: A Strategy Applicable to Diverse Targets
Volume: 21
Issue: 13
Author(s): Qingxin Li*Congbao Kang*
Affiliation:
- Guangdong Provincial Engineering Laboratory of Biomass High Value Utilization, Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou 510316,China
- Experimental Drug Development Centre (EDDC), Agency for Science, Technology and Research (A*STAR), 10 Biopolis Road, Chromos, #05-01, Singapore 138670,Singapore
Keywords:
Fragment-based drug discovery, Structural biology, Hit identification, Fragment growth, Druggability, NMR, Biophysics,
X-ray crystallography.
Abstract: Fragment-Based Drug Discovery (FBDD) is a strategy to develop potent lead molecules
and is frequently used in drug discovery projects of the pharmaceutical industry. This method starts
from identifying a small-molecule fragment, which usually binds weakly to the target and follows
with a hit-to-lead step in which the fragment is grown into potent molecules that bind tightly to the
target to affect its function. Quite a few drugs and compounds in clinical trials are developed using
this approach, making FBDD a powerful strategy in drug discovery. FBDD can be applied to multiple
targets and the hit rate in screening can be used in target druggability assessment. In this minireview,
we provide a summary of the development of FBDD. In addition to giving a brief summary
of the methods used in fragment screening, we highlight some methods that are critical in fragment
growth. Biophysical methods and careful chemical modification of the fragments are the key elements
in FBDD. We show several strategies that can be utilized in FBDD. We emphasize that
NMR spectroscopy such as 19F-NMR and 1H-15N-HSQC experiment and X-ray crystallography are
important in FBDD due to their roles in fragment screening and understanding the binding modes
of the fragment hits, which provides a strategy for fragment growth.