One Scaffold, Three Binding Modes: Novel and Selective Pteridine Reductase 1 Inhibitors Derived from Fragment Hits Discovered by Virtual Screening†
| Autor: | David A. Robinson, William N. Hunter, Emma Shanks, Alan H. Fairlamb, Ian H. Gilbert, Daniel Spinks, Iain T. Collie, Chidochangu P. Mpamhanga, Lindsay B. Tulloch, Paul G. Wyatt, Julie A. Frearson, Ruth Brenk |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Stereochemistry Trypanosoma brucei brucei Drug Evaluation Preclinical Molecular Conformation 01 natural sciences Article Substrate Specificity 03 medical and health sciences Oxidoreductase Drug Discovery Animals Humans Computer Simulation Benzothiazoles Enzyme Inhibitors 030304 developmental biology chemistry.chemical_classification 0303 health sciences Virtual screening biology 010405 organic chemistry Drug discovery Biological activity 3. Good health 0104 chemical sciences Pteridine reductase Enzyme Protein–ligand docking chemistry Enzyme inhibitor biology.protein Molecular Medicine Benzimidazoles Oxidoreductases |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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