A comparative molecular field analysis study of obtusifoliol 14α-methyl demethylase inhibitors †

This report describes the development of a Comparative Molecular Field Analysis (CoMFA) model from a set of obtusifoliol 14α-methyl demethylase (DM) inhibitors to aid in the design of herbicides targeting sterol biosynthesis. CoMFA is a three-dimensional (3-D) quantitative structure–activity relationship (QSAR) method that is useful in the probing of receptor binding sites when experimental structure data are unavailable. Conformational analysis and SAR of some rigid and active analogs were used to build the initial model using the active analog hypothesis. The model was subsequently used to design compounds that retain the active site shape requirements, but incorporate physical properties that favor soil-applied herbicidal action. In addition, a second-generation CoMFA model incorporating the newly designed inhibitors was developed and represents the current understanding of the DM binding site. This model was derived from a pharmacophore developed from two methods, the active analog approach as well as from the Catalyst program. The fact that two independent methods produced a similar pharmacophore strengthens the validity of the model. © 1999 Society of Chemical Industry