3SRR

S. aureus Dihydrofolate Reductase complexed with novel 7-aryl-2,4-diaminoquinazolines


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines.

Li, X.Hilgers, M.Cunningham, M.Chen, Z.Trzoss, M.Zhang, J.Kohnen, L.Lam, T.Creighton, C.G C, K.Nelson, K.Kwan, B.Stidham, M.Brown-Driver, V.Shaw, K.J.Finn, J.

(2011) Bioorg Med Chem Lett 21: 5171-5176

  • DOI: https://doi.org/10.1016/j.bmcl.2011.07.059
  • Primary Citation of Related Structures:  
    3SQY, 3SR5, 3SRQ, 3SRR, 3SRS, 3SRU, 3SRW

  • PubMed Abstract: 

    Dihydrofolate reductase (DHFR) inhibitors such as trimethoprim (TMP) have long played a significant role in the treatment of bacterial infections. Not surprisingly, after decades of use there is now bacterial resistance to TMP and therefore a need to develop novel antibacterial agents with expanded spectrum including these resistant strains. In this study, we investigated the optimization of 2,4-diamnoquinazolines for antibacterial potency and selectivity. Using structure-based drug design, several 7-aryl-2,4-diaminoquinazolines were discovered that have excellent sub-100 picomolar potency against bacterial DHFR. These compounds have good antibacterial activity especially on gram-positive pathogens including TMP-resistant strains.


  • Organizational Affiliation

    Trius Therapeutics, San Diego, CA 92121, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydrofolate reductaseA [auth X]167Staphylococcus aureusMutation(s): 0 
Gene Names: folA
EC: 1.5.1.3
UniProt
Find proteins for P0A017 (Staphylococcus aureus)
Explore P0A017 
Go to UniProtKB:  P0A017
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0A017
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAP
Query on NAP

Download Ideal Coordinates CCD File 
C [auth X]NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
Q20
Query on Q20

Download Ideal Coordinates CCD File 
B [auth X]3-(2,4-diamino-6-methylquinazolin-7-yl)-4-ethoxybenzaldehyde
C18 H18 N4 O2
BDVALXKNVWZHIQ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
Q20 BindingDB:  3SRR Ki: 0.24 (nM) from 1 assay(s)
Binding MOAD:  3SRR Ki: 0.24 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.317α = 90
b = 79.317β = 90
c = 107.394γ = 120
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2011-08-31 
  • Deposition Author(s): Hilgers, M.

Revision History  (Full details and data files)

  • Version 1.0: 2011-08-31
    Type: Initial release
  • Version 1.1: 2011-10-19
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations