6N1T

Toxoplasma gondii TS-DHFR in complex with selective inhibitor 3

6N1T の概要

• エントリーDOI: 10.2210/pdb6n1t/pdb
• 関連するPDBエントリー: 4eil 6aog 6aoh 6aoi 6n1s
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• 機能のキーワード: toxoplasma gondii, dhfr, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Toxoplasma gondii
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 132247.63

構造登録者

Hopper, A.T.,Brockman, A.,Wise, A.,Gould, J.,Barks, J.,Radke, J.B.,Sibley, L.D.,Zou, Y.,Thomas, S.B. (登録日: 2018-11-11, 公開日: 2019-01-23, 最終更新日: 2023-10-11)

主引用文献

Hopper, A.T.,Brockman, A.,Wise, A.,Gould, J.,Barks, J.,Radke, J.B.,Sibley, L.D.,Zou, Y.,Thomas, S.
Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis.
J. Med. Chem., 62:1562-1576, 2019

PubMed Abstract: A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC of 1.57 ± 0.11 nM and a hDHFR to TgDHFR selectivity ratio of 196, making it 89-fold more potent and 16-fold more selective than 1. Compound 3 was highly effective in control of acute infection by highly virulent strains of T. gondii in the murine model, and it possesses the best combination of selectivity, potency, and prerequisite drug-like properties to advance into IND-enabling, preclinical development.

PubMed: 30624926
DOI: 10.1021/acs.jmedchem.8b01754

実験手法

X-RAY DIFFRACTION (3.5 Å)