PDBsum entry: 1boz

Oxidoreductase

PDB id: 1boz

Contents

Protein chain

186 a.a. *

Ligands

NDP

PRD

Waters ×125

* Residue conservation analysis

PDB id:

1boz

Name:

Oxidoreductase

Title:

Structure-based design and synthesis of lipophilic 2,4- diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductase and potential antitumor agents

Structure:

Protein (dihydrofolate reductase). Chain: a. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606

Resolution:

2.10Å R-factor: 0.202

Authors:

A.Gangjee,A.P.Vidwans,A.Vasudevan,S.F.Queener,R.L.Kisliuk, V.Cody,R.Li,N.Galitsky,J.R.Luft,W.Pangborn

Key ref:

A.Gangjee et al. (1998). Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents. J Med Chem, 41, 3426-3434. PubMed id: 9719595 DOI: 10.1021/jm980081y

Date:

06-Aug-98 Release date: 12-Aug-98

Protein chain

P00374  (DYR_HUMAN) -  Dihydrofolate reductase

Seq: 187 a.a.

Struc: 186 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

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

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

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

 Gene Ontology (GO) functional annotation 

• Cellular component: cellular_component (3 terms)
• Biological process: oxidation-reduction process (12 terms)
• Biochemical function: drug binding (6 terms)

reference

DOI no: 10.1021/jm980081y

J Med Chem 41:3426-3434 (1998)

PubMed id: 9719595

Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents.

A.Gangjee, A.P.Vidwans, A.Vasudevan, S.F.Queener, R.L.Kisliuk, V.Cody, R.Li, N.Galitsky, J.R.Luft, W.Pangborn.

ABSTRACT

The synthesis and biological activities of 14 6-substituted 2,4-diaminoquinazolines are reported. These compounds were designed to improve the cell penetration of a previously reported series of 2,4-diamino-6-substituted-pyrido[2,3-d]pyrimidines which had shown significant potency and remarkable selectivity for Toxoplasma gondii dihydrofolate reductase (DHFR), but had much lower inhibitory effects on the growth of T. gondii cells in culture. The target N9-H analogues were obtained via regiospecific reductive amination of the appropriate benzaldehydes with 2,4,6-triaminoquinazoline, which, in turn, was synthesized from 2,4-diamino-6-nitroquinazoline. The N9-CH3 analogues were synthesized via a regiospecific reductive methylation of the corresponding N9-H precursors. The compounds were evaluated as inhibitors of DHFR from human, Pneumocystis carinii, T. gondii, rat liver, Lactobacillus casei, and Escherichia coli, and selected analogues were evaluated as inhibitors of the growth of tumor cells in culture. These analogues displayed potent T. gondii DHFR inhibition as well as inhibition of the growth of T. gondii cells in culture. Further, selected analogues were potent inhibitors of the growth of tumor cells in culture in the in vitro screening program of the National Cancer Institute with GI50s in the nanomolar and subnanomolar range. Crystallographic data for the ternary complex of hDHFR-NADPH and 2,4-diamino-6-[N-(2', 5'-dimethoxybenzyl)-N-methylamino]pyrido[2,3-d]pyrimidine, 1c, reveal the first structural details for a reversed N9-C10 folate bridge geometry as well as the first conformational details of a hybrid piritrexim-trimetrexate analogue.