Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br>
A series of benzothiazolium-based hemicyanines (3a-3f) have been synthesized. Evaluation of their photophysical properties shows that they exhibit improved photophysical characteristics. In comparison with the available commercial MitoTrackers, the new probes revealed an enhanced Stokes shift (Δλ ∼ 80 nm) and minimized aggregation for increased sensitivity. The synthesized probes are found to exhibit excellent selectivity for mitochondrial staining in an oligodendrocyte cell line. Probes show almost no fluorescence in aqueous environments, while the fluorescence is increased by ∼10-fold in organic solvents, making it possible for mitochondrial imaging without the need for post-staining washing. Since the absorption peaks of probes are close to the laser wavelengths of 561 and 640 nm on a commercial confocal microscope, e.g.3a exhibits λabs ∼ 620 nm and λem ∼ 702 nm, they could be useful probes for mitochondrial tracking in live cells.
The value of time-dependent toxicity (TDT) data in predicting mixture
toxicity was examined. Single chemical (A and B) and mixture (A + B) toxicity
tests using Microtox® were conducted with inhibition of
bioluminescence (Vibrio fischeri) being quantified after 15, 30
and 45-min of exposure. Single chemical and mixture tests for 25 sham
(A1:A2) and 125 true (A:B) combinations had a minimum
of seven duplicated concentrations with a duplicated control treatment for each
test. Concentration/response (x/y) data were
fitted to sigmoid curves using the five-parameter logistic minus one parameter
(5PL-1P) function, from which slope, EC25, EC50,
EC75, asymmetry, maximum effect, and
r2 values were obtained for each chemical and
mixture at each exposure duration. Toxicity data were used to calculate
percentage-based TDT values for each individual chemical and mixture of each
combination. Predicted TDT values for each mixture were calculated by averaging
the TDT values of the individual components and regressed against the observed
TDT values obtained in testing, resulting in strong correlations for both sham
(r2 = 0.989, n = 25) and true
mixtures (r2 = 0.944, n = 125).
Additionally, regression analyses confirmed that observed mixture TDT values
calculated for the 50% effect level were somewhat better correlated with
predicted mixture TDT values than at the 25 and 75% effect levels.
Single chemical and mixture TDT values were classified into five levels in order
to discern trends. The results suggested that the ability to predict mixture TDT
by averaging the TDT of the single agents was modestly reduced when one agent of
the combination had a positive TDT value and the other had a minimal or negative
TDT value.
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