9DC8

Mtb GuaB dCBS in complex with inhibitor G1

9DC8 の概要

• エントリーDOI: 10.2210/pdb9dc8/pdb
• 分子名称: Inosine-5'-monophosphate dehydrogenase, INOSINIC ACID, N-(6-chloropyridin-3-yl)-N~2~-(1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)-L-alaninamide, ... (5 entities in total)
• 機能のキーワード: mycobacterium tuberculosis, guab, impdh, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45046.30

構造登録者

Harris, S.F.,Wu, P. (登録日: 2024-08-25, 公開日: 2024-11-27, 最終更新日: 2025-01-29)

主引用文献

Zhou, Y.,Aliagas, I.,Wang, S.,Li, C.S.,Liu, Z.,Bowman, C.M.,Burdick, D.J.,Clark, K.R.,Dening, T.J.,Flygare, J.,Ganti, A.,Girgis, H.S.,Hanan, E.J.,Harris, S.F.,Hu, C.,Kapadia, S.B.,Koehler, M.F.T.,Lai, T.,Liang, J.,Liu, X.,Ma, F.,Mao, J.,Nicolai, J.,Sims, J.,Unhayaker, S.,Wai, J.,Wang, X.,Wu, P.,Xu, Y.,Yen, C.W.,Zhang, R.,Elfert, T.F.,Tan, M.W.,Kofoed, E.M.,Crawford, T.D.
Discovery of potent dihydro-oxazinoquinolinone inhibitors of GuaB for the treatment of tuberculosis.
Bioorg.Med.Chem.Lett., 117:130026-130026, 2025

PubMed Abstract: Tuberculosis is the leading cause of death from an infectious disease, and is caused by Mycobacterium tuberculosis (M.tb). More than 1 billion people worldwide are thought to harbor an M.tb infection. The multidrug therapy that represents the current standard of care requires a minimum of four months of dosing and drug resistant Mycobacterium tuberculosis treatment regimens are significantly longer. Inosine-5'-monophosphate dehydrogenase (GuaB) is the enzyme that performs the rate-limiting step in de novo guanine nucleotide biosynthesis that is critical for growth and viability of bacteria including M.tb. The development of a novel antibiotic that inhibits GuaB could combine with existing therapies in novel ways and thereby contribute to effective therapeutic regimens for the treatment of tuberculosis. Here we describe the discovery of structurally distinct small molecule GuaB inhibitors that are potent against M.tb H37Ra and H37Rv strains and have desirable safety and ADME profiles.

PubMed: 39536836
DOI: 10.1016/j.bmcl.2024.130026

実験手法

X-RAY DIFFRACTION (1.6 Å)