Structural and Physico-Chemical Interpretation (SPCI) of QSAR Models and Its Comparison with Matched Molecular Pair Analysis

This paper describes the Structural
and Physico-Chemical Interpretation
(SPCI) approach, which is an extension of a recently reported method
for interpretation of quantitative structure–activity relationship
(QSAR) models. This approach can efficiently be used to reveal structural
motifs and the major physicochemical factors affecting the investigated
properties. Its efficacy was demonstrated both on the classical Free–Wilson
data set and on several data sets with different end points (permeability
of the blood–brain barrier, fibrinogen receptor antagonists,
acute oral toxicity). Structure–activity patterns extracted
from QSAR models with SPCI were in good correspondence with experimentally
observed relationships and molecular docking, regardless of the machine
learning method used. Comparison of SPCI with the matched molecular
pair (MMP) method clearly shows an advantage of our approach over
MMP, especially for small or structurally diverse data sets. The developed
approach has been implemented in the SPCI software tool with a graphical
user interface, which is publicly available at http://qsar4u.com/pages/sirms_qsar.php.