Projects per year
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 language | English |
---|---|
Pages (from-to) | 4454-4465 |
Number of pages | 12 |
Journal | Journal of Medicinal Chemistry |
Volume | 52 |
Issue number | 14 |
DOIs | |
Publication status | Published - 23 Jul 2009 |
Keywords
- PARASITE LEISHMANIA-MAJOR
- ANTIOPPORTUNISTIC INFECTION AGENTS
- HUMAN AFRICAN TRYPANOSOMIASIS
- PROTEIN-LIGAND DOCKING
- MOLECULAR-DOCKING
- DRUG DISCOVERY
- THYMIDYLATE SYNTHASE
- SCORING FUNCTIONS
- DIFFRACTION DATA
- FORCE-FIELD
Fingerprint
Dive into the research topics of 'One Scaffold, Three Binding Modes: Novel and Selective Pteridine Reductase 1 Inhibitors Derived from Fragment Hits Discovered by Virtual Screening'. Together they form a unique fingerprint.Projects
- 3 Finished
-
Aref#d: 19815. Wellcome Trust Centre for Drug Discovery (Strategic Award)
Fairlamb, A. (Investigator), Ferguson, M. (Investigator) & Frearson, J. (Investigator)
1/01/08 → 31/12/12
Project: Research
-
Aref#d: 19401. Structure, specificity and mechanism of biosynthetic enzymes in trypanosomatids and inhibitor discovery of essential microbial functions (Programme Grant)
Hunter, B. (Investigator)
1/11/07 → 31/12/13
Project: Research
-
Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)
Fairlamb, A. (Investigator)
1/10/06 → 30/09/17
Project: Research