A Different Method for Steric Field Evaluation in CoMFA Improves Model Robustness

The all-grid probe Lennard-Jones 6−12 potential, typically used
as steric descriptor in CoMFA, has been
replaced by the volumes of van der Waals envelopes intersections
between the probe-atom and the ligand
molecules under investigation. The intersection volumes present a
smoother distance dependence that
overcomes the problems arising from formulation of a precise alignment
and docking into the 3D lattice. A
CoMFA-type application on a set of 78 steroid aromatase inhibitors with
different grid and probe-atom
characteristics suggests an improved model robustness for the new
steric field in comparison with the classical
6−12 potential. Predefined cut-off and
“minimum  sigma” values are not required.
Systematic variation
of the 3D lattice position leads to lower variations of cross-validated
r-squared (q2LOO) at all
levels of model
complexity, which can be reduced with exclusion of some “interior”
points. The relative simplicity and
inexpensive computational demands make this steric field a promising
alternative for routine CoMFA-based 3D-QSAR analyses.