Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 14, Pages 4454-4465Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm900414x
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Funding
- Biotechnology and Biological Sciences Research Council [BBS/B/14434] Funding Source: Medline
- Wellcome Trust [083481, 079838, WT077705, 082596] Funding Source: Medline
- Biotechnology and Biological Sciences Research Council [BBS/B/14434] Funding Source: researchfish
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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.
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