7opj | pdb_00007opj

Trypanosoma brucei PTR1 (TbPTR1) in complex with pyrimethamine

spinqualitylabelsall models 7opj, resolution 1.34Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7opj is a 4 chain structure with sequence from Trypanosoma brucei brucei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.34Å Ligands: ACT, CP6, GOL, NAP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function O76290_TRYBB Publication Abstract from PubMed Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine-nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the TbDHFR inhibitor cycloguanil (CYC) also targets TbPTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both TbPTR1 and TbDHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target TbPTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to TbPTR1. The structural comparison between PYR and CYC binding modes to TbPTR1 and TbDHFR provided key insights for the future design of dual inhibitors for HAT therapy. Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase.,Tassone G, Landi G, Linciano P, Francesconi V, Tonelli M, Tagliazucchi L, Costi MP, Mangani S, Pozzi C Pharmaceuticals (Basel). 2021 Jun 30;14(7). pii: ph14070636. doi:, 10.3390/ph14070636. PMID:34209148 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Pteridine reductase

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