Library Design Strategies To Accelerate Fragment‐Based Drug Discovery

Abstract

Fragment‐based drug discovery (FBDD) has become an established approach for the generation of early lead candidates. However, despite its success and inherent advantages, hit‐to‐candidate progression for FBDD is not necessarily faster than that of traditional high‐throughput screening. Thus, new technology‐driven library design strategies have emerged as a means to facilitate more efficient fragment screening and/or subsequent fragment‐to‐hit chemistry. This minireview discusses such strategies, which cover the use of labeled fragments for NMR spectroscopy, X‐ray crystallographic screening of specialized fragments, covalent linkage for mass spectrometry, dynamic combinatorial chemistry, and fragments optimized for easy elaboration.

Fragment-based covalent ligand discovery

“…1). We would like to note that several excellent reviews focusing on covalent fragment library design have recently been published, 1,2,[17][18][19] and we will not comment on this here.…”

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence

“…However, this paradigm has been changing based on incremental experience in FBDD acquired in the last years and considering the facilitation of fragment screening and/ or subsequent fragment optimization chemistry (187,188). Nowadays, several strategies exist, which cover the use of labeled fragments for nuclear magnetic resonance (NMR) spectroscopy, covalent linkage for mass spectrometry, dynamic combinatorial chemistry, X-ray crystallographic screening of specialized fragments and fragments optimized for easy elaboration (189).…”

Fragment‐Based Drug Discovery for RNA Targets

“…Researchers from Astex Pharmaceuticals proposed the rule of threes (RO3) guidelines back in 2003, [51] but other considerations such as three-dimensionality and ease of chemical elaboration of fragment hits are also relevant. [52,53] As fragment hits generally are low-affinity binders they need to be synthetically linked, grown, or merged, it is more efficient when the library consists of molecules with multiple functional groups as growth vectors. [11] The fragments themselves could also be synthesized via "poised scaffolds" that allows for easier synthesis of analogues of hits for further SAR studies.…”