title: The ways and means of fragment-based drug design.
abstract: Fragment-based drug design (FBDD) has emerged as a mainstream approach for the rapid and efficient identification of building blocks that can be used to develop high-affinity ligands against protein targets. One of the strengths of FBDD is the relative ease and low cost of the primary screen to identify fragments that bind. However, the fragments that emerge from primary screens often have low affinities, with KDvalues in the high μM to mM range, and a significant challenge for FBDD is to develop the initial fragments into more potent ligands. Successful fragment elaboration often requires co-structures of the fragments bound to their target proteins, as well as a range of biophysical and biochemical assays to track potency and efficacy. These challenges have led to the development of specific chemical strategies for the elaboration of weakly-binding fragments into more potent "hits" and lead compounds. In this article we review different approaches that have been employed to meet these challenges and describe some of the strategies that have resulted in several fragment-derived compounds entering clinical trials.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Doak
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia. Electronic address: martin.scanlon@monash.edu.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Scanlon
mesh_terms: D015195:Drug Design; D006801:Humans; D008024:Ligands; D058990:Molecular Targeted Therapy; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D011506:Proteins
keywords: Medicinal chemistry; Protein; Screening; Structure-based drug design