Five quantitative spectroscopic data-activity relationships (QSDAR) models
for 50 steroidal inhibitors binding to aromatase enzyme have been developed
based on simulated C-13 nuclear magnetic resonance (NMR) data. Three of th
e models were based on comparative spectral analysis (CoSA), and the two ot
her models were based on comparative structurally assigned spectral analysi
s (CoSASA). A CoSA QSDAR model based on five principal components had an ex
plained variance (r(2)) of 0.78 and a leave-one-out (LOO) cross-validated v
ariance (q(2)) of 0.71. A CoSASA model that used the assigned C-13 NMR chem
ical shifts from a steroidal backbone at five selected positions gave an r(
2) of 0.75 and a q2 of 0.66. The C-13 NMR chemical shifts from atoms in the
steroid template position 9, 6, 3, and 7 each had correlations greater tha
n 0.6 with the relative binding activity to the aromatase enzyme. All five
QSDAR models had explained and cross-validated variances that were better t
han the explained and cross-validated variances from a five structural para
meter quantitative structure-activity relationship (QSAR) model of the same
compounds. QSAR modeling suffers from errors introduced by the assumptions
and approximations used in partial charges, dielectric constants, and the
molecular alignment process of one structural conformation. One postulated
reason that the variances of QSDAR models are better than the QSAR models i
s that C-13 NMR spectral data, based on quantum mechanical principles, are
more reflective of binding than the QSAR model's calculated electrostatic p
otentials and molecular alignment process. The QSDAR models provide a rapid
, simple way to model the steroid inhibitor activity in relation to the aro
matase enzyme.