Template CoMFA: The 3D-QSAR Grail?

Template
CoMFA, a novel alignment methodology for training or test
set structures in 3D-QSAR, is introduced. Its two most significant
advantages are its complete automation and its ability to derive a
single combined model from multiple structural series affecting a
biological target. Its only two inputs are one or more “template”
structures having 3D coordinates that share some Cartesian space,
as may result from X-ray crystallography or pharmacophoric hypothesis,
and one or more connectivity-only SAR tables associated with a common
target. Template CoMFA also overcomes the major disadvantages of both
existing 3D-QSAR alignment methodologies, specifically the tedium
and subjectivity of familiar ad hoc approaches, and the awkwardness,
occasional physicochemical heresies, and structural scope limitations
of the purely topomer approach. The template CoMFA algorithms are
described, and two of its application classes are presented. The first
class, general models of binding to factor Xa and P38 map kinase,
uses crystallographic structures as templates, with the encouraging
result that the statistical qualities of each of these two combined
models are equivalent to those of their constituent individual series
models. The second, 15 data sets originally collected for validation
of topomer CoMFA, with arbitrary structures as templates, confirms
that the modeling power of template CoMFA resembles that of its predecessors.