title: Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility.
abstract: An approach for designing bioactive small molecules has been developed in which de novo structure-based ligand design (SBLD) was focused on regions of chemical space accessible using a diversity-oriented synthetic approach. The approach was exploited in the design and synthesis of a focused library of platensimycin analogues in which the complex bridged ring system was replaced with a series of alternative ring systems. The affinity of the resulting compounds for the C163Q mutant of FabF was determined using a WaterLOGSY competition binding assay. Several compounds had significantly improved affinity for the protein relative to a reference ligand. The integration of synthetic accessibility with ligand design enabled focus to be placed on synthetically-accessible regions of chemical space that were relevant to the target protein under investigation.
authors.affiliation: School of Chemistry, University of Leeds, West Yorkshire, LS2 9JT, UK. a.s.nelson@leeds.ac.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Fisher
authors.forename: Ramkrishna
authors.initials: R
authors.lastname: Basak
authors.forename: Arnout P
authors.initials: AP
authors.lastname: Kalverda
authors.forename: Colin W G
authors.initials: CW
authors.lastname: Fishwick
authors.forename: W Bruce
authors.initials: WB
authors.lastname: Turnbull
authors.forename: Adam
authors.initials: A
authors.lastname: Nelson
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000218:Adamantane / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062365:Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054889:Fatty Acid Synthase, Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D062365:Aminobenzoates; D000813:Anilides; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D008024:Ligands; D000123:Acetyltransferases; C557137:fabF protein, E coli; D054889:Fatty Acid Synthase, Type II; D000218:Adamantane; C510909:platensimycin