PDBsum entry 4lae

Oxidoreductase/oxidoreductase inhibitor

PDB id: 4lae

Contents

Protein chain

157 a.a.

Ligands

NAP

1VM

Waters ×118

PDB id:

4lae

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Structure-based design of new dihydrofolate reductase antibacterial agents: 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines

Structure:

Dihydrofolate reductase. Chain: x. Synonym: dhfr. Engineered: yes

Source:

Staphylococcus aureus. Organism_taxid: 1280. Gene: fola. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

1.69Å R-factor: 0.195 R-free: 0.225

Authors:

M.T.Hilgers

Key ref:

T.Lam et al. (2014). Structure-based design of new dihydrofolate reductase antibacterial agents: 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines. J Med Chem, 57, 651-668. PubMed id: 24428639 DOI: 10.1021/jm401204g

Date:

19-Jun-13 Release date: 19-Feb-14

Protein chain

P0A017  (DYR_STAAU) -  Dihydrofolate reductase from Staphylococcus aureus

Seq: 159 a.a.

Struc: 157 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 = NAP) corresponds exactly) = 7,8-dihydrofolate (Bound ligand (Het Group name = 1VM) matches with 42.86% similarity) + NADPH + H(+)

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

reference

DOI no: 10.1021/jm401204g

J Med Chem 57:651-668 (2014)

PubMed id: 24428639

Structure-based design of new dihydrofolate reductase antibacterial agents: 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines.

T.Lam, M.T.Hilgers, M.L.Cunningham, B.P.Kwan, K.J.Nelson, V.Brown-Driver, V.Ong, M.Trzoss, G.Hough, K.J.Shaw, J.Finn.

ABSTRACT

A new series of dihydrofolate reductase (DHFR) inhibitors, the 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized for antibacterial potency and enzyme selectivity. The most potent inhibitors in this series contained a five-membered heterocycle at the 2-position of the benzimidazole, leading to highly potent and selective compounds that exploit the differences in the size of a binding pocket adjacent to the NADPH cofactor between the bacterial and human DHFR enzymes. Typical of these compounds is 7-((2-thiazol-2-yl)benzimidazol-1-yl)-2,4 diaminoquinazoline, which is a potent inhibitor of S. aureus DHFR (Ki = 0.002 nM) with 46700-fold selectivity over human DHFR. This compound also has high antibacterial potency on Gram-positive bacteria with an MIC versus wild type S. aureus of 0.0125 μg/mL and a MIC versus trimethoprim-resistant S. aureus of 0.25 μg/mL. In vivo efficacy versus a S. aureus septicemia was demonstrated, highlighting the potential of this new series.