2WD8

PTERIDINE REDUCTASE 1 (PTR1) FROM TRYPANOSOMA BRUCEI IN COMPLEX WITH NADP AND DDD00071204

Summary for 2WD8

• Entry DOI: 10.2210/pdb2wd8/pdb
• Related: 2C7V 2VZ0 2WD7
• Descriptor: PTERIDINE REDUCTASE, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: short-chain dehydrogenase/reductase, drug discovery, oxidoreductase, trypanosomatids, pteridine reductase, methotrexate resistance
• Biological source: TRYPANOSOMA BRUCEI BRUCEI
• Total number of polymer chains: 4
• Total formula weight: 117767.92

Authors

Robinson, D.A.,Wyatt, P.G.,Spinks, D.,Brenk, R. (deposition date: 2009-03-20, release date: 2009-06-30, Last modification date: 2023-12-13)

Primary citation

Mpamhanga, C.P.,Spinks, D.,Tulloch, L.B.,Shanks, E.J.,Robinson, D.A.,Collie, I.T.,Fairlamb, A.H.,Wyatt, P.G.,Frearson, J.A.,Hunter, W.N.,Gilbert, I.H.,Brenk, R.
One Scaffold, Three Binding Modes: Novel and Selective Pteridine Reductase 1 Inhibitors Derived from Fragment Hits Discovered by Virtual Screening.
J.Med.Chem., 52:4454-, 2009

PubMed 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.

PubMed: 19527033
DOI: 10.1021/JM900414X

Experimental method

X-RAY DIFFRACTION (2.1 Å)