title: Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: discovery, synthesis, and characterization of their binding mode by protein crystallography.
abstract: Trypanothione reductase (TryR) is a genetically validated drug target in the parasite  Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences,  University of Dundee , Dow Street, Dundee DD1 5EH, U.K.
authors.forename: Stephen
authors.initials: S
authors.lastname: Patterson
authors.forename: Magnus S
authors.initials: MS
authors.lastname: Alphey
authors.forename: Deuan C
authors.initials: DC
authors.lastname: Jones
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Shanks
authors.forename: Ian P
authors.initials: IP
authors.lastname: Street
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008024:Ligands; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D008024:Ligands; D011799:Quinazolines; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase