Current perspectives in fragment-based lead discovery (FBLD)

• Published in: Essays in biochemistry Vol. 61; no. 5; p. 453
• Main Authors: Lamoree, Bas, Hubbard, Roderick E
• Format: Journal Article
• Language: English
• Published: England 08.11.2017
• Subjects: Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - therapeutic use; Clinical Trials as Topic; Combinatorial Chemistry Techniques; Drug Design; Drug Discovery - methods; Humans; Indoles - therapeutic use; Molecular Docking Simulation; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Nitrophenols - chemical synthesis; Nitrophenols - therapeutic use; Piperazines - chemical synthesis; Piperazines - therapeutic use; Protein Binding; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - therapeutic use; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - therapeutic use; Thermodynamics; chemical biology; drug discovery and design; fragment based lead discovery
• ISSN: 1744-1358
• DOI: 10.1042/EBC20170028

It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most 'conventional' targets in drug discovery such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, such as disruption of protein-protein interactions. The main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. In this essay, we overview current practice in the methods and discuss how they have had an impact in lead discovery - generating a large number of fragment-derived compounds that are in clinical trials and two medicines treating patients. In addition, we discuss some of the more recent applications of the methods in chemical biology - providing chemical tools to investigate biological molecules, mechanisms and systems.