8JFB

V1/S quadruple mutant Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with compound 4 (B21588), NADPH and dUMP

8JFB の概要

• エントリーDOI: 10.2210/pdb8jfb/pdb
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, 3-[4-[[2,4-bis(azanyl)-6-ethyl-pyrimidin-5-yl]methyl]phenyl]benzoic acid, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• 機能のキーワード: dhfr, dihydrofolate reductase, plasmodium falciparum, malaria, 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: 146620.27

構造登録者

Vanichtanankul, J.,Saeyang, T.,Vitsupakorn, D.,Saepua, S.,Thongpanchang, C.,Yuthavong, Y.,Kamchonwongpaisan, S.,Hoarau, M. (登録日: 2023-05-17, 公開日: 2023-08-23, 最終更新日: 2023-10-04)

主引用文献

Hoarau, M.,Sermmai, P.,Varatthan, T.,Thiabma, R.,Jantra, T.,Rattanajak, R.,Vitsupakorn, D.,Vanichtanankul, J.,Saepua, S.,Yuthavong, Y.,Thongpanchang, C.,Kamchonwongpaisan, S.
Discovery of rigid biphenyl Plasmodium falciparum DHFR inhibitors using a fragment linking strategy.
Rsc Med Chem, 14:1755-1766, 2023

PubMed Abstract: dihydrofolate reductase (DHFR), a historical target for antimalarials, has been considered compromised due to resistance inducing mutations caused by pyrimethamine () overexposure. The clinical candidate has demonstrated that inhibitors could efficiently target both -sensitive and -resistant parasites through careful drug design. Yet, clinical development has been limited by its pharmacokinetic profile, incompatible with single dose regimen. Herein, we report the design of new DHFR inhibitors using fragment-based design, aiming at improved lipophilicity and overall drug-like properties. Fragment-based screening identified hits binding in the pABA site of the enzyme. Using structure-guided design, hits were elaborated into leads by fragment linking with 2,4-diaminopyrimidine. Resulting compounds display nM range inhibition of both drug-sensitive and resistant DHFR, high selectivity against the human isoform, drug-like lipophilicity and metabolic stability. Compound 4 and its ester derivative 3 kill blood stage TM4/8.2 parasite at nM concentrations while showing no toxicity against Vero cells.

PubMed: 37731689
DOI: 10.1039/d3md00242j

実験手法

X-RAY DIFFRACTION (2.65 Å)