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: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 14 Pg. 4454-65 (Jul 23 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19527033 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzimidazoles
• Benzothiazoles
• Enzyme Inhibitors
• aminobenzothiazole compound
• benzimidazole
• Oxidoreductases
• pteridine reductase

Topics

• Animals
• Benzimidazoles (chemistry, metabolism, pharmacology)
• Benzothiazoles (chemistry, metabolism, pharmacology)
• Computer Simulation
• Drug Evaluation, Preclinical (methods)
• Enzyme Inhibitors (chemistry, metabolism, pharmacology)
• Humans
• Models, Molecular
• Molecular Conformation
• Oxidoreductases (antagonists & inhibitors, chemistry, metabolism)
• Substrate Specificity
• Trypanosoma brucei brucei (enzymology)