title: Combining Molecular Scaffolds from FDA Approved Drugs: Application to Drug Discovery.
abstract: We have enumerated all linear combinations of ring systems from FDA approved drugs, up to three rings in length and up to four bonds linkers to give an in silico database of approximately 14 million molecules. This virtual library was compared with molecular databases of published and commercially available compounds to assess the prevalence of drug ring combinations in modern medicinal chemistry and to identify areas of under-represented, but clinically validated, chemical space. From the 10 trillion molecular comparisons, we found that less than 1% of the possible combinations of drug ring systems appear in commercially available libraries. This key observation highlights significant opportunities to design new fragment-like and lead-like libraries aimed at improving success rates and reducing risk in small molecule drug discovery, as, based on our previous analysis ( Taylor J. Med. Chem. 2014 , 57 , 5845 - 5849 ), approximately 70% of all new drugs are made up of only ring systems that have been used in existing drugs.
authors.affiliation: UCB , 216 Bath Road, Slough, SL1 3WE, U.K.
authors.forename: Richard D
authors.identifier: 0000-0002-4808-5010
authors.initials: RD
authors.lastname: Taylor
authors.affiliation: Bohicket Pharma Consulting LLC , 2556 Seabrook Island Road, Seabrook Island, South Carolina 29455, United States.
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.affiliation: UCB , 216 Bath Road, Slough, SL1 3WE, U.K.
authors.forename: Alastair D G
authors.initials: AD
authors.lastname: Lawson
mesh_terms: D017277:Drug Approval / Q000331:legislation & jurisprudence*; D055808:Drug Discovery; D054852:Small Molecule Libraries; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D054852:Small Molecule Libraries