Subject: Re:Enhancing CoMFA:free program release

From: David Larson <[email-masked]>
Date: Thu, 17 Dec 1998 08:59:46 -0600

Arthur Wang recently posted a message to CCL announcing avaiability of
SPL programs which "improve" CoMFA analyses by exhaustively searching
the possible orientations and placements of molecules on the lattice and
using that which gives the highest q^2.  Users should be aware that when
this is done, that highest q^2 ceases to be a valid test statistic for
the significance of the model and no longer accurately reflects the
expected external predictivity, just as is the case for variable
selection methods in general( see U Norinder J. Chemonetrics 1996, 10,
95-105 and recent reports by other groups).  This is because compounds
are no longer completely "left out" of the analysis - each contributes
to identifying the highest q^2.

A lattice shift represents a random perturbation of the CoMFA
descriptors.  Though neither the highest nor the lowest q^2 value are of
interest in and of themselves, the AOS and APS programs may nonetheless
be useful for determining the distribution of values and hence how
robust a particular model (the scheme used to align each molecule with
the others) is.  When this is done, however, the appropriate test
statistic is the median or mode q^2 or, better, the mean cross-validated
standard error and the q^2 calculated therefrom. 

Lattice placements which give q^2 values at either extreme - high or low
- are misleading and therefore undesirable.  It turns out, however, that
good representative lattice orientations can reliably be obtained simply
by applying ORIENT BEST to a prototypical molecular (usually the most
extended of the more active compounds) and aligning other molecules in
the training set on that prototype (RD Clark, M Cline & TW Heritage
(1998) Making 3D QQSAR Both Simple and Robust, 215 ACS Natl Meeting,
Abstract COMP 057). In fact, this is now the default option in the
DATABASE ALIGNMENT dialog in SYBYL QSAR. 

Bob Clark
Tripos Inc.
1699 S. Hanley Road
St. Louis MO 63144

[email-masked]