PDBsum entry 4ixe

Oxidoreductase/inhibitor

PDB id: 4ixe

Contents

Protein chain

206 a.a.

Ligands

IXE

NDP

Waters ×114

PDB id:

4ixe

Name:

Oxidoreductase/inhibitor

Title:

Pcdhfr-NADPH-270

Structure:

Dihydrofolate reductase. Chain: d. Engineered: yes

Source:

Pneumocystis carinii. Organism_taxid: 4754. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.54Å R-factor: 0.179 R-free: 0.220

Authors:

V.Cody

Key ref:

A.Gangjee et al. (2013). 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. PubMed id: 23627352 DOI: 10.1021/jm400086g

Date:

25-Jan-13 Release date: 29-May-13

Protein chain

P16184  (DYR_PNECA) -  Dihydrofolate reductase from Pneumocystis carinii

Seq: 206 a.a.

Struc: 206 a.a.

Enzyme reactions

• Enzyme class: E.C.1.5.1.3 - dihydrofolate reductase.
• Pathway: Folate Coenzymes
• Reaction: (6S)-5,6,7,8-tetrahydrofolate + NADP⁺ = 7,8-dihydrofolate + NADPH + H⁺

(6S)-5,6,7,8-tetrahydrofolate + NADP(+) (Bound ligand (Het Group name = NDP) corresponds exactly) = 7,8-dihydrofolate + NADPH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm400086g

J Med Chem 56:4422-4441 (2013)

PubMed id: 23627352

Design, synthesis, and molecular modeling of novel pyrido[2,3-d]pyrimidine analogues as antifolates; application of Buchwald-Hartwig aminations of heterocycles.

A.Gangjee, O.A.Namjoshi, S.Raghavan, S.F.Queener, R.L.Kisliuk, V.Cody.

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.