The p110
DER=0> isoform of the class IA PI3Ks was recently genetically vali
date
d as a promising target foranticancer therapy. However, up to now, only one compoun
d (
PIK75 = 1) has been reporte
d as a verypotent an
d selective inhibitor of this isoform. The lack of a 3D structure for this enzyme has clearly hin
dere
dthe
discovery of new p110
selective compoun
ds. In view of this, we combine
d target-base
d (homologymo
deling) an
d ligan
d-base
d (3D-QSAR) approaches in an attempt to
define an integrate
d interaction mo
delfor p110
inhibition. Twenty-five analogues of
1 were
docke
d within the putative p110
bin
ding site, an
dthe molecular alignment generate
d was subsequently use
d to
derive QSAR mo
dels base
d on scoring function,free energy of bin
ding, CoMFA. an
d CoMSIA. The pre
dictive power of these mo
dels was then analyze
dusing a challenging test set of 5 compoun
ds. CoMSIA, an
d particularly CoMFA, mo
dels were foun
d tooutperform the other metho
ds, pre
dicting accurately the potency of 100% of the compoun
ds in the test set,thereby vali
dating our p110
homology mo
del for use in further
drug
development.