title: Route to three-dimensional fragments using diversity-oriented synthesis.
abstract: Fragment-based drug discovery (FBDD) has proven to be an effective means of producing high-quality chemical ligands as starting points for drug-discovery pursuits. The increasing number of clinical candidate drugs developed using FBDD approaches is a testament of the efficacy of this approach. The success of fragment-based methods is highly dependent on the identity of the fragment library used for screening. The vast majority of FBDD has centered on the use of sp(2)-rich aromatic compounds. An expanded set of fragments that possess more 3D character would provide access to a larger chemical space of fragments than those currently used. Diversity-oriented synthesis (DOS) aims to efficiently generate a set of molecules diverse in skeletal and stereochemical properties. Molecules derived from DOS have also displayed significant success in the modulation of function of various "difficult" targets. Herein, we describe the application of DOS toward the construction of a unique set of fragments containing highly sp(3)-rich skeletons for fragment-based screening. Using cheminformatic analysis, we quantified the shapes and physical properties of the new 3D fragments and compared them with a database containing known fragment-like molecules.
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Alvin W
authors.initials: AW
authors.lastname: Hung
authors.forename: Alex
authors.initials: A
authors.lastname: Ramek
authors.forename: Yikai
authors.initials: Y
authors.lastname: Wang
authors.forename: Taner
authors.initials: T
authors.lastname: Kaya
authors.forename: J Anthony
authors.initials: JA
authors.lastname: Wilson
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.forename: Damian W
authors.initials: DW
authors.lastname: Young
mesh_terms: D016208:Databases, Factual; D015195:Drug Design; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D006841:Hydrocarbons, Aromatic