The
p110
pha.gif" BORDER=0> isoform of the class IA PI3Ks was recently genetically validated as a
promising target foranticancer thera
py. However, u
p to now, only one com
pound (
PIK75 = 1) has been re
ported as a very
potent and selective inhibitor of this isoform. The lack of a 3D structure for this enzyme has clearly hinderedthe discovery of new
p110
pha.gif" BORDER=0> selective com
pounds. In view of this, we combined target-based (homologymodeling) and ligand-based (3D-QSAR) a
pproaches in an attem
pt to define an integrated interaction modelfor
p110
pha.gif" BORDER=0> inhibition. Twenty-five analogues of
1 were docked within the
putative
p110
pha.gif" BORDER=0> binding site, andthe molecular alignment generated was subsequently used to derive QSAR models based on scoring function,free energy of binding, CoMFA. and CoMSIA. The
predictive
power of these models was then analyzedusing a challenging test
set of 5 com
pounds. CoMSIA, and
particularly CoMFA, models were found toout
perform the other methods,
predicting accurately the
potency of 100% of the com
pounds in the test
set,thereby validating our
p110
pha.gif" BORDER=0> homology model for use in further drug develo
pment.