4IXF

pcDHFR-269 F69N variant

4IXF の概要

• エントリーDOI: 10.2210/pdb4ixf/pdb
• 関連するPDBエントリー: 3cd2 4IXE 4IXG
• 分子名称: Dihydrofolate reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, N~6~-methyl-N~6~-[4-(propan-2-yl)phenyl]pyrido[2,3-d]pyrimidine-2,4,6-triamine, ... (4 entities in total)
• 機能のキーワード: pcdhfr-269-nadph f69n ternary complex, reductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Pneumocystis carinii
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24939.27

構造登録者

Cody, V. (登録日: 2013-01-25, 公開日: 2013-05-29, 最終更新日: 2023-09-20)

主引用文献

Gangjee, A.,Namjoshi, O.A.,Raghavan, S.,Queener, S.F.,Kisliuk, R.L.,Cody, V.
Design, Synthesis, and Molecular Modeling of Novel Pyrido[2,3-d]pyrimidine Analogues As Antifolates; Application of Buchwald-Hartwig Aminations of Heterocycles.
J.Med.Chem., 56:4422-4441, 2013

PubMed Abstract: Opportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, pj), Toxoplasma gondii (T. gondii, tg), and Mycobacterium avium (M. avium, ma) are the principal causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of pjDHFR and tgDHFR make the design of inhibitors challenging. A novel series of pyrido[2,3-d]pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald-Hartwig coupling reaction of substituted anilines with pivaloyl protected 2,4-diamino-6-bromo-pyrido[2,3-d]pyrimidine was successfully explored to synthesize these analogues. Compound 26 was the most selective inhibitor with excellent potency against pjDHFR. Molecular modeling studies with a pjDHFR homology model explained the potency and selectivity of 26. Structural data are also reported for 26 with pcDHFR and 16 and 22 with variants of pcDHFR.

PubMed: 23627352
DOI: 10.1021/jm400086g

実験手法

X-RAY DIFFRACTION (1.7 Å)