Fragment-based approaches in drug discovery and chemical biology.
Fragment-based approaches to finding novel small molecules that bind to proteins are now firmly established in drug discovery and chemical biology. Initially developed primarily in a few centers in the biotech and pharma industry, this methodology has now been adopted widely in both the pharmaceutical industry and academia. After the initial success with kinase targets, the versatility of this approach has now expanded to a broad range of different protein classes. Herein we describe recent fragment-based approaches to a wide range of target types, including Hsp90, β-secretase, and allosteric sites in human immunodeficiency virus protease and fanesyl pyrophosphate synthase. The role of fragment-based approaches in an academic research environment is also examined with an emphasis on neglected diseases such as tuberculosis. The development of a fragment library, the fragment screening process, and the subsequent fragment hit elaboration will be discussed using examples from the literature.
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Duncan E
DE
Scott
Anthony G
AG
Coyne
Sean A
SA
Hudson
Chris
C
Abell
D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D057166:High-Throughput Screening Assays / Q000379:methods* / Q000639:trends; D006801:Humans; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D054852:Small Molecule Libraries / Q000138:chemical synthesis
D010446:Peptide Fragments; D054852:Small Molecule Libraries