One Scaffold, Three Binding Modes: Novel and Selective Pteridine Reductase 1 Inhibitors Derived from Fragment Hits Discovered by Virtual Screening

Chidochangu P. Mpamhanga, Daniel Spinks, Lindsay B. Tulloch, Emma J. Shanks, David A. Robinson, Iain T. Collie, Alan H. Fairlamb, Paul G. Wyatt, Julie A. Frearson, William N. Hunter, Ian H. Gilbert, Ruth Brenk*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)

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 or 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.

Original languageEnglish
Pages (from-to)4454-4465
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number14
DOIs
Publication statusPublished - 23 Jul 2009

Keywords

  • MOLECULAR-DOCKING
  • SCORING FUNCTIONS
  • FORCE-FIELD
  • PROTEIN-LIGAND DOCKING
  • DRUG DISCOVERY
  • HUMAN AFRICAN TRYPANOSOMIASIS
  • ANTIOPPORTUNISTIC INFECTION AGENTS
  • DIFFRACTION DATA
  • THYMIDYLATE SYNTHASE
  • PARASITE LEISHMANIA-MAJOR

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