8F82

Crystal Structure of Dihydrofolate reductase (DHFR) from Mycobacterium ulcerans Agy99 in complex with NADP and inhibitor MAM845

8F82 の概要

• エントリーDOI: 10.2210/pdb8f82/pdb
• 分子名称: Dihydrofolate reductase, 3-{2-[3-({(6M)-2,4-diamino-6-[3-(trifluoromethyl)phenyl]pyrimidin-5-yl}oxy)propoxy]phenyl}propanoic acid, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (6 entities in total)
• 機能のキーワード: ssgcid, structural genomics, seattle structural genomics center for infectious disease, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Mycobacterium ulcerans
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 20453.55

構造登録者

Seattle Structural Genomics Center for Infectious Disease,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (登録日: 2022-11-21, 公開日: 2023-12-13, 最終更新日: 2024-11-27)

主引用文献

Andrade Meirelles, M.,Almeida, V.M.,Sullivan, J.R.,de Toledo, I.,Dos Reis, C.V.,Cunha, M.R.,Zigweid, R.,Shim, A.,Sankaran, B.,Woodward, E.L.,Seibold, S.,Liu, L.,Mian, M.R.,Battaile, K.P.,Riley, J.,Duncan, C.,Simeons, F.R.C.,Ferguson, L.,Joji, H.,Read, K.D.,Lovell, S.,Staker, B.L.,Behr, M.A.,Pilli, R.A.,Counago, R.M.
Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium , Two Emerging Human Pathogens.
J.Med.Chem., 67:19143-19164, 2024

PubMed Abstract: Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on , a malarial DHFR inhibitor. We identified compound , a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: and . This study underscores the potential of compound as a promising candidate for the validation of DHFR as an effective treatment against NTM infections.

PubMed: 39468773
DOI: 10.1021/acs.jmedchem.4c01594

実験手法

X-RAY DIFFRACTION (1.2 Å)