9B2E

DHNA associated with an inhibitor

9B2E の概要

• エントリーDOI: 10.2210/pdb9b2e/pdb
• 分子名称: 7,8-dihydroneopterin aldolase, 2-amino-8-sulfanyl-1,9-dihydro-6H-purin-6-one (3 entities in total)
• 機能のキーワード: protein complex, lyase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27298.71

構造登録者

Czeczot, A.M.,Silva, E.E.D.,Timmers, L.F.S.M.,Machado, P.,Basso, L.A.,Bizarro, C.V. (登録日: 2024-03-15, 公開日: 2025-02-19)

主引用文献

Czeczot, A.M.,Muniz, M.N.,Perello, M.A.,Silva, E.E.D.,Timmers, L.F.S.M.,Berger, A.,Gonzalez, L.C.,Arrache Goncalves, G.,Moura, S.,Machado, P.,Bizarro, C.V.,Basso, L.A.
Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity.
J Enzyme Inhib Med Chem, 39:2388207-2388207, 2024

PubMed Abstract: The crystallographic structure of the FolB enzyme from (FolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of FolB. These compounds exhibited IC values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the H37Rv strain were evaluated. Compound exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting FolB, an attractive molecular target for TB drug development.

PubMed: 39140692
DOI: 10.1080/14756366.2024.2388207

実験手法

X-RAY DIFFRACTION (1.95 Å)