Template CoMFA offers an unprecedentedly robust and automatic means for generating a unified 3D-QSAR model from multiple X-ray (or pharmacophoric) templates and diverse structural series. Because such strong claims require strong proof, an unusually extensive validation study (perhaps the largest ever for a new CADD methodology) has been performed for template CoMFA, 74 different targets including templates extracted from 509 PDB files. Useful models (r2 greater than .9 or q2 greater than .2) were effortlessly obtained for 70 of these 74 targets.Such an X-ray-constrained 3D-QSAR methodology might help to bridge the developing chasm between structure-based and ligand-based analyses. A CoMFA model could expand the interpretability of an individual X-ray structure by superimposing a summary of the ligand SAR � or an X-ray structure could suggest structural extrapolations most likely to exploit a promising 3D-QSAR trend. Other new possibilities might include one-off predictions that have meaningful confidence limits; or even guidance in evaluating docking poses when X-ray structures are unavailable. Results from exploring some of these possibilities will be presented.

Might template CoMFA integrate structure-based and ligand-based design?

248th National Meeting (2014)

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