8RHT

Crystal Structure of Trypanosoma brucei DHFR in complex with the cofactor and inhibitor P25

これはPDB形式変換不可エントリーです。

8RHT の概要

• エントリーDOI: 10.2210/pdb8rht/pdb
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4,4,7,8-tetramethyl-10~{H}-[1,3,5]triazino[1,2-a]benzimidazol-2-amine, ... (4 entities in total)
• 機能のキーワード: trypanosoma brucei, dhfr, dihydrofolate reductase, cofactor, nadph, inhibitor, oxidoreductase
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27578.48

構造登録者

Pozzi, C.,Mangani, S.,Landi, G. (登録日: 2023-12-17, 公開日: 2024-11-20)

主引用文献

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

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: 38953453
DOI: 10.1021/acsinfecdis.4c00113

実験手法

X-RAY DIFFRACTION (2.9 Å)