3SRU

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

Summary for 3SRU

• Entry DOI: 10.2210/pdb3sru/pdb
• Related: 3SQY 3SR5 3SRQ 3SRR 3SRS 3SRW
• Descriptor: Dihydrofolate reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, N-[3'-(2,4-diaminoquinazolin-7-yl)-4'-ethoxybiphenyl-3-yl]methanesulfonamide, ... (4 entities in total)
• Functional Keywords: dihydrofolate reductase, dhfr, drug design, enzyme inhibitors, folate, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 1
• Total formula weight: 20540.02

Authors

Hilgers, M. (deposition date: 2011-07-07, release date: 2011-08-31, Last modification date: 2024-02-28)

Primary citation

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.
Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines.
Bioorg.Med.Chem.Lett., 21:5171-5176, 2011

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.

PubMed: 21831637
DOI: 10.1016/j.bmcl.2011.07.059

Experimental method

X-RAY DIFFRACTION (1.7 Å)