title: Evolutionary chemistry approach toward finding novel inhibitors of the type 2 diabetes target glucose-6-phosphate translocase.
abstract: A genetic algorithm (GA), driven by experimentally determined biological activities as a feedback fitness function, was used to propose novel small molecules as inhibitors of glucose-6-phosphate translocase (G6PT) in iterative rounds of evolutionary optimization. A straightforward polymer-supported synthetic sequence was implemented to synthesize molecules proposed by the GA, and the biological activities of the compounds were determined by a microsomal assay. Additional compound design strategies were integrated, such as Tanimoto similarity-based selection of starting materials and transfer of favored structure elements into a new chemical scaffold to identify more active and selective inhibitors.
authors.affiliation: Morphochem AG, Gmunder Strasse 37-37a, 81379 München, Germany. silke.braeuer@morphochem.de
authors.forename: Silke
authors.initials: S
authors.lastname: Bräuer
authors.forename: Michael
authors.initials: M
authors.lastname: Almstetter
authors.forename: Walfrido
authors.initials: W
authors.lastname: Antuch
authors.forename: Dirk
authors.initials: D
authors.lastname: Behnke
authors.forename: Roswitha
authors.initials: R
authors.lastname: Taube
authors.forename: Patrick
authors.initials: P
authors.lastname: Furer
authors.forename: Sibylle
authors.initials: S
authors.lastname: Hess
mesh_terms: D000818:Animals; D017920:Antiporters / Q000037:antagonists & inhibitors*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: D017920:Antiporters; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D009004:Monosaccharide Transport Proteins; C503531:SLC37A4 protein, human; D005952:Glucose-6-Phosphatase; D005947:Glucose