8YQ9

Quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS V1/S) complexed with FB6, NADPH and dUMP

これはPDB形式変換不可エントリーです。

8YQ9 の概要

• エントリーDOI: 10.2210/pdb8yq9/pdb
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-[4-[3-[2,4-bis(azanyl)-6-ethyl-pyrimidin-5-yl]oxypropoxy]phenyl]benzoic acid, ... (6 entities in total)
• 機能のキーワード: dihydrofolate reductase, thymidylate synthase, antifolate, plasmodium falciparum, biphenyl, fragment, oxidoreductase
• 由来する生物種: Plasmodium falciparum (malaria parasite P. falciparum)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 146924.56

構造登録者

Vanichtanankul, J.,Vitsupakorn, D.,Saeyang, T.,Arwon, U.,Hoarau, M.,Decharuangsilp, S.,Kamchonwongpaisan, S.,Yuthavong, Y. (登録日: 2024-03-19, 公開日: 2024-09-11)

主引用文献

Decharuangsilp, S.,Arwon, U.,Sooksai, N.,Rattanajak, R.,Saeyang, T.,Vitsupakorn, D.,Vanichtanankul, J.,Yuthavong, Y.,Kamchonwongpaisan, S.,Hoarau, M.
Novel flexible biphenyl Pf DHFR inhibitors with improved antimalarial activity.
Rsc Med Chem, 15:2496-2507, 2024

PubMed Abstract: As pregnant women and young children remain the first victims of malaria worldwide, the search for new antimalarials has been focusing on compounds with a high safety profile and extended efficacy. In a previous study, a rigid biphenyl DHFR inhibitor was developed by fragment-based screening, displaying sub nM enzyme inhibition but poor antiparasitic activity, presumably due to its low flexibility. Here, we report a new series of compounds that combines the biphenyl fragment with a flexible linker. Interestingly, their mode of binding differs from previously reported compounds, taking advantage of strong hydrophobic interaction. The new flexible biphenyl compounds show overall improved antiparasitic activity compared to rigid ones, with the best compound displaying a 2 nM antiplasmodial IC and suitable drug-like properties. This confirms the importance of compound flexibility for antimalarial activity and opens the way to new opportunities for antimalarial drug design.

PubMed: 39026651
DOI: 10.1039/d4md00197d

実験手法

X-RAY DIFFRACTION (2.4 Å)