Lifetime FRET
HTS. (A) Pilot screening with LOPAC library. Compounds
that reduced the FRET efficiency below 3SD (black line) were selected
for further characterization. Nine hit compounds with reproducible
FRET change were identified from the pilot screens (red). (B) Dose
response curves of three HbS hit compounds (panel A, red circles).
Fluorescently labeled HbS samples were dispensed into a 1536-well
plate and treated separately with DMSO or the three hit compounds,
chlormezanone, gabazine, and phosphoramidon disodium, in a dose-dependent
manner from 0.1 to 1000 μM for 2 h at room temperature and then
vacuum degassed for 10 min, and then donor lifetimes were measured
using a fluorescence plate reader. (C) Effective diameter of HbS in
the presence and absence of hit compounds from DLS measured at 90°.
HbS samples (25 μM) were incubated separately with hit compounds
(100 μM) or DMSO only for 2 h at room temperature and degassed
with argon for 5 min, and then DLS measurements were taken at room
temperature. Hypothesis testing was performed using parametric ANOVA
with Dunnett’s multiple comparison testing. *p-value < 0.05; **p-value < 0.01; ***p-value < 0.001.