Perspectives on Fragment-based Drug Discovery: A Strategy Applicable to Diverse Targets

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-⁵N-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.

Keywords: Biophysics; Druggability; Fragment growth; Fragment-based drug discovery; Hit identification; NMR; Structural biology; X-ray crystallography..