Molecular docking and three-dimensional quantitative structure-activity relationship studies on the binding modes of herbicidal 1-(substituted phenoxyacetoxy)alkylphosphonates to the E1 component of pyruvate dehydrogenase.

Molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies on the title compounds were performed to explore the possible inhibitory mechanism. To determine the probable binding conformations of the title phosphonate derivatives, the most potent compound 12 was chosen as a standard template and docked into the active site of PDHc E1. On the basis of the binding conformations, highly predictive 3D-QSAR models were developed with q2 values of 0.872 and 0.873 for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), respectively. The predictive abilities of these models were validated by using a set of compounds that were not included in the training set. Both the CoMFA and the CoMSIA field distributions are in good agreement with the spatial and electronic structural characteristics of the binding groove of PDHc E1 selected in this work. Mapping the 3D-QSAR models to the active site of PDHc E1 provides new insight into the protein-inhibitor interaction mechanism, which is most likely valuable and applicable for designing highly active compounds in the future.