title: One scaffold, three binding modes: novel and selective pteridine reductase 1 inhibitors derived from fragment hits discovered by virtual screening.
abstract: The enzyme pteridine reductase 1 (PTR1) is a potential target for new compounds to treat human African trypanosomiasis. A virtual screening campaign for fragments inhibiting PTR1 was carried out. Two novel chemical series were identified containing aminobenzothiazole and aminobenzimidazole scaffolds, respectively. One of the hits (2-amino-6-chloro-benzimidazole) was subjected to crystal structure analysis and a high resolution crystal structure in complex with PTR1 was obtained, confirming the predicted binding mode. However, the crystal structures of two analogues (2-amino-benzimidazole and 1-(3,4-dichloro-benzyl)-2-amino-benzimidazole) in complex with PTR1 revealed two alternative binding modes. In these complexes, previously unobserved protein movements and water-mediated protein-ligand contacts occurred, which prohibited a correct prediction of the binding modes. On the basis of the alternative binding mode of 1-(3,4-dichloro-benzyl)-2-amino-benzimidazole, derivatives were designed and selective PTR1 inhibitors with low nanomolar potency and favorable physicochemical properties were obtained.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Chidochangu P
authors.initials: CP
authors.lastname: Mpamhanga
authors.forename: Daniel
authors.initials: D
authors.lastname: Spinks
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Tulloch
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Shanks
authors.forename: David A
authors.initials: DA
authors.lastname: Robinson
authors.forename: Iain T
authors.initials: IT
authors.lastname: Collie
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.forename: William N
authors.initials: WN
authors.lastname: Hunter
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D052160:Benzothiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D014346:Trypanosoma brucei brucei / Q000201:enzymology
chemical_list: D001562:Benzimidazoles; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; C523775:aminobenzothiazole compound; C031000:benzimidazole; D010088:Oxidoreductases; C085592:pteridine reductase