R. Gozalbes et al., Prediction of quinolone activity against Mycobacterium avium by molecular topology and virtual computational screening, ANTIM AG CH, 44(10), 2000, pp. 2764-2770
We conducted a quantitative structure-activity relationship study using a d
atabase of 158 quinolones previously tested against Mycobacterium avium-M.
intracellulare complex in order to develop a model capable of predicting th
e activity of new quinolones against the M. avium-M, intracellulare complex
in vitro. Topological indices were used as structural descriptors and were
related to anti-M. avium-M. intracellulare complex activity by using the l
inear discriminant analysis (LDA) statistical technique. The discriminant e
quation thus obtained correctly classified 137 of the 158 quinolones. inclu
ding 37 of a test group of 44 randomly chosen compounds, This model was the
n applied to 24 quinolones, including recently developed fluoroquinolones,
whose MICs were subsequently determined in vitro by using the Alamar blue m
icroplate assay; the biological results confirmed the model's predictions.
The MICs of these 24 quinolones were then treated by multilinear regression
(MLR) to establish a model capable of classifying them according to their
in vitro activities. Using this model, a good correlation between measured
and predicted MICs was found (r(2) = 0.88; r(cv)(2) [cross-validation corre
lation] = 0.82), Moxifloxacin, sparfloxacin, and gatifloxacin were the most
potent against the M. avium- M. intracellulare complex. with MICs of 0.2,
0.4, and 0.9 mu g/ml, respectively. Finally, virtual modifications of these
three drugs were evaluated in LDA and MLR models in order to determine the
importance of different substituents in their activity, We conclude that t
he combination of molecular-topology methods, LDA, and MLR provides an exce
llent tool fur the design of new quinolone structures with enhanced activit
y.