In 1963 Hansch and Fujita invented 2D QSAR, which signaled the conversion of drug design from chemists' intuition and ease of synthesis to property-based considerations aided by computer analysis. Left as by-standers were researchers who ignored the use of statistical analysis with computers or who ignored the importance of hydrophobicity to drug potency. Some twenty-five years later Richard Cramer III and colleagues united molecular modelling and QSAR with the CoMFA method that showed that it is possible to correlate the potency of exisiting and forecast the potency of untested compounds with their 3D properties. Left as by-standers were researchers who focussed on complex descriptions of 3D properties or who ignored the use of multivariate statistical methods. Five years after that, Martin and colleagues showed that it is possible to use a computer to identify the 3D pharmacophores present in a set of diverse molecules, thus providing a starting hypothesis for CoMFA analysis. Left as by-standers were those who developed methods that required the user to specify the corresponding atoms in the molecules or who focussed on the 3D structures of the molecules, not their properties in 3D space. In each of these examples, the paradigm shift was catalyzed by the focus of the investigators to solve a problem.

Three paradigm shifts in computer-assisted drug design: The inventors and by-standers

246th National Meeting (2013)

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