Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.5.1.3 (
dihydrofolate reductase
)
5,819
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
WR99210, a former antimalarial drug candidate now widely used for the selection of
Plasmodium
transfectants, selectively targets the parasite
dihydrofolate reductase
thymidine synthase bifunctional enzyme (DHFR-TS) but not human
DHFR
, which is not fused with TS. Accordingly, WR99210 and plasmids expressing human
dhfr
have become valued tools for the genetic modification of parasites in the laboratory. Concerns over the ineffectiveness of WR99210 from some sources encouraged us to investigate the biological and chemical differences of supplies from two different companies (compounds
1
and
2
). Compound
1
proved effective at low nanomolar concentrations against
Plasmodium falciparum
parasites, whereas compound
2
was ineffective even at micromolar concentrations. Intact and fragmented mass spectra indicated identical molecular formulae of the unprotonated (free base) structures of
1
and
2
; however, the compounds displayed differences by thin layer chromatography, reverse phase high performance liquid chromatography, and ultraviolet-visible spectroscopy, indicating important isomeric differences. Structural evaluations by
1
H,
13
C, and
15
N nuclear magnetic resonance spectroscopy confirmed
1
as WR99210 and
2
as a dihydrotriazine regioisomer. Induced fit, computational docking models showed that
1
binds tightly and specifically in the
P. falciparum
DHFR
active site whereas
2
fits poorly to the active site in loose and varied orientations. Stocks and concentrates of WR99210 should be monitored for the presence of regioisomer
2
, particularly when they are not supplied as the hydrochloride
salt
or are exposed to basic conditions that may promote rearrangement. Absorption spectroscopy can serve for assays of the unrearranged and rearranged triazines.
...
PMID:Regioisomerization of antimalarial drug WR99210 explains the inactivity of a commercial stock. 3307 47
<< Previous
1
2
3
4
5
6
7
