A new binding model for structurally diverse ALS inhibitors

Abstract

Acetolactate synthase (ALS) has been a very attractive target for herbicides for the last decade. There are several ALS inhibitors in commercial use spanning the world-wide market. In this study, the common structural features within a subset of ALS inhibitors were investigated by molecular graphics and quantum chemical calculations. Satisfactory results were obtained with model calculations based on the presumption that the relative location of the inhibitor azine moiety and some receptor cationic group remained fixed. The cationic group was assumed to interact with an acidic group in each of the inhibitors. This model explains many aspects of ALS inhibitors (sulfonylureas, triazolopyrimidines, pyrimidyl ethers and other classes) such as: (1) the common structural feature among the different classes of ALS inhibitors, (2) the substituent effects in the hydrophobic moiety of each class and (3) the structure-activity relationships of the acidic moiety of each class. These are significant achievements for a model based on in-vivo herbicidal activity and gas-phase calculations, but the model also has its limitations: (1) Only compounds with acidic groups and azine moieties can be addressed, (2) the structure- activity relationships of the hydrophobic moiety are not yet fully understood and (3) only a qualitative prediction of activity levels is possible. A preliminary trial of ligand design predicted the novel skeleton of an ALS inhibitor that was published independently from this study.