9ONI

Crystal structure of dihydrofolate reductase (DHFR) from the filarial nematode W. bancrofti in complex with NADPH and methotrexate (MTX)

9ONI の概要

• エントリーDOI: 10.2210/pdb9oni/pdb
• 関連するPDBエントリー: 8E4F 9MLM 9MLT
• 分子名称: dihydrofolate reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, METHOTREXATE, ... (4 entities in total)
• 機能のキーワード: dihydrofolate reductases, nadph, antifolate, oxidoreductase
• 由来する生物種: Wuchereria bancrofti
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23280.27

構造登録者

Frey, K.M.,Kwarteng, S.,Goodey, N.M. (登録日: 2025-05-15, 公開日: 2025-08-27, 最終更新日: 2025-09-03)

主引用文献

Kwarteng, S.,Wilhelm, J.,Salama, M.,Salama, M.,Hollander, K.,Anderson, K.S.,Goodey, N.M.,Frey, K.M.
A virtual screening strategy to repurpose antifolate compounds as W.bancrofti DHFR inhibitors.
Bioorg.Med.Chem.Lett., 129:130370-130370, 2025

PubMed Abstract: Lymphatic filariasis, caused by Wuchereria bancrofti, remains a global health challenge. The enzyme Wuchereria bancrofti dihydrofolate reductase (WbDHFR) is a potential therapeutic target due to DHFR's critical role in folate metabolism and DNA synthesis. In this study, we employed a virtual screening workflow to repurpose antifolate compounds as WbDHFR inhibitors. Using structural data from the Protein Data Bank, we constructed a library of 194 antifolates and docked them to the WbDHFR folate binding site. Compounds methotrexate, TSD001, TSD10, and TSD25, with docking scores ranging from -9 to -8 kcal/mol, were selected for experimental validation. Inhibition assays demonstrated nanomolar activity with methotrexate and low micromolar activity with TSD001 (K = 1 μM). Crystallographic studies revealed high-resolution structures of WbDHFR in complex with methotrexate (2.4 Å), TSD001 (2.9 Å), TSD10 (1.8 Å) and TSD25 (2.1 Å), providing detailed insights into binding interactions. Major interactions common for the inhibitors include hydrogen bonds with Glu32. These findings highlight the effectiveness of the virtual screening workflow and establish a foundation for optimizing these antifolate compounds for WbDHFR inhibition. This workflow can be applied to other parasitic DHFR enzymes, advancing drug discovery efforts against neglected tropical diseases.

PubMed: 40812516
DOI: 10.1016/j.bmcl.2025.130370

実験手法

X-RAY DIFFRACTION (2.44 Å)