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The all-grid probe Lennard-Jones 6−12 potential, typically used as steric descriptor in CoMFA, has been replaced by the volumes of van der Waals envelopes intersections between the probe-atom and the ligand molecules under investigation.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.