1 research outputs found
Design of Novel FLT-3 Inhibitors Based on Dual-Layer 3D-QSAR Model and Fragment-Based Compounds <i>in Silico</i>
FMS-like tyrosine kinase 3 (FLT-3) is strongly correlated
with
acute myeloid leukemia, but no FLT-3–inhibitor cocomplex structure
is available
to assist the design of therapeutic inhibitors. Hence, we propose
a dual-layer 3D-QSAR model for FLT-3 that integrates the pharmacophore,
CoMFA, and CoMSIA. We then coupled the model with the fragment-based
design strategy to identify novel FLT-3 inhibitors. In the first layer,
the previously established model, Hypo02, was evaluated in terms of
its correlation coefficient (<i>r</i>), RMS, cost difference,
and configuration cost, with values of 0.930, 1.24,
106.45, and 16.44, respectively. Moreover, Fischer’s cross-validation
test of data generated by Hypo02 yielded a 98% confidence level, and
the validation of the testing set yielded a best <i>r</i> value of 0.87. The features of Hypo02 were separated into two parts
and then used to screen the MiniMaybridge fragment compound database.
Nine novel FLT-3 inhibitors were generated in this layer. In the second
layer, Hypo02 was subjected to an alignment rule to generate CoMFA-
and CoMSIA-based models, for which the partial least-squares validation
method was utilized. The values of <i>q</i><sup>2</sup>, <i>r</i><sup>2</sup>, and predictive <i>r</i><sup>2</sup> were 0.58, 0.98, and 0.76, respectively, derived
from the CoMFA model with steric and electrostatic fields. The CoMSIA
model with five different fields yielded values of 0.54, 0.97, and
0.76 for <i>q</i><sup>2</sup>, <i>r</i><sup>2</sup>, and predictive <i>r</i><sup>2</sup>, respectively. The
CoMFA and CoMSIA models were used to constrain 3D structures of the
nine novel FLT-3 inhibitors. This dual-layer 3D-QSAR model constitutes
a valuable tool to easily and quickly screen and optimize novel potential
FLT-3 inhibitors for the treatment of acute myeloid leukemia