8RHX
Crystal Structure of Trypanosoma brucei PTR1 in complex with the cofactor and inhibitor P32
This is a non-PDB format compatible entry.
Summary for 8RHX
| Entry DOI | 10.2210/pdb8rhx/pdb |
| Related | 8RHT 8RHU 8RHV 8RHW |
| Descriptor | Pteridine reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1-[4,6-bis(chloranyl)-1~{H}-benzimidazol-2-yl]guanidine, ... (5 entities in total) |
| Functional Keywords | trypanosoma brucei, ptr1, pteridine reductase, cofactor, nadph, inhibitor, oxidoreductase |
| Biological source | Trypanosoma brucei brucei |
| Total number of polymer chains | 4 |
| Total formula weight | 127339.07 |
| Authors | |
| Primary citation | Francesconi, V.,Rizzo, M.,Pozzi, C.,Tagliazucchi, L.,Konchie Simo, C.U.,Saporito, G.,Landi, G.,Mangani, S.,Carbone, A.,Schenone, S.,Santarem, N.,Tavares, J.,Cordeiro-da-Silva, A.,Costi, M.P.,Tonelli, M. Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti- Trypanosoma brucei Agents. Acs Infect Dis., 10:2755-2774, 2024 Cited by PubMed Abstract: Folate enzymes, namely, dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) are acknowledged targets for the development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. Based on the amino dihydrotriazine motif of the drug Cycloguanil (Cyc), a known inhibitor of both folate enzymes, we have identified two novel series of inhibitors, the 2-amino triazino benzimidazoles () and 2-guanidino benzimidazoles (), as their open ring analogues. Enzymatic screening was carried out against PTR1, DHFR, and thymidylate synthase (TS). The crystal structures of DHFR and PTR1 in complex with selected compounds experienced in both cases a substrate-like binding mode and allowed the rationalization of the main chemical features supporting the inhibitor ability to target folate enzymes. Biological evaluation of both series was performed against and and the toxicity against THP-1 human macrophages. Notably, the 5,6-dimethyl-2-guanidinobenzimidazole resulted to be the most potent ( = 9 nM) and highly selective DHFR inhibitor, 6000-fold over PTR1 and 394-fold over DHFR. The 5,6-dimethyl tricyclic analogue , despite showing a lower potency and selectivity profile than , shared a comparable antiparasitic activity against in the low micromolar domain. The dichloro-substituted 2-guanidino benzimidazoles and revealed their potent and broad-spectrum antitrypanosomatid activity affecting the growth of and parasites. Therefore, both chemotypes could represent promising templates that could be valorized for further drug development. PubMed: 38953453DOI: 10.1021/acsinfecdis.4c00113 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.48 Å) |
Structure validation
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