 |
PDBsum entry 3cse
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
3cse
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structure-Guided development of efficacious antifungal agents targeting candida glabrata dihydrofolate reductase.
|
|
|
Authors
|
|
J.Liu,
D.B.Bolstad,
A.E.Smith,
N.D.Priestley,
D.L.Wright,
A.C.Anderson.
|
|
|
Ref.
|
|
Chem Biol, 2008,
15,
990-996.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents
and has emerged as a critical target for drug discovery. Over the past several
years, we have been developing a class of propargyl-linked antifolates as
antimicrobials and hypothesized that these compounds could be effective
inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially
screened a small collection of these inhibitors and found modest levels of
potency. Subsequently, we determined the crystal structure of C. glabrata DHFR
bound to a representative inhibitor with data to 1.6 A resolution. Using this
structure, we designed and synthesized second-generation inhibitors. These
inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display
greater than 2000-fold levels of selectivity over the human enzyme, and inhibit
the growth of C. glabrata at levels observed with clinically employed
therapeutics.
|
|
|
|
|
|
|
