Combined molecular docking and QSAR study of fused heterocyclic herbicide inhibitors of D1 protein in photosystem II of plants


Cinnoline, pyridine, pyrimidine, and triazine herbicides were found be inhibitors of the D1 protein in photosystem II (D1 PSII) electron transport of plants. The photosystem II inhibitory activity of these herbicides, expressed by experimental \(\hbox {pIC}_{50}\) values, was modeled by a docking and quantitative structure-activity relationships study. A conformer ensemble for each of the herbicide structure was generated using the MMFF94s force field. These conformers were further employed in a docking approach, which provided new information about the rational “active conformations” and various interaction patterns of the herbicide derivatives with D1 PSII. The most “active conformers” from the docking study were used to calculate structural descriptors, which were further related to the inhibitory experimental \(\hbox {pIC}_{50}\) values by multiple linear regression (MLR). The dataset was divided into training and test sets according to the partition around medoids approach, taking 27% of the compounds from the entire series for the test set. Variable selection was performed using the genetic algorithm, and several criteria were checked for model performance. WHIM and GETAWAY geometrical descriptors (position of substituents and moieties in the molecular space) were found to contribute to the herbicidal activity. The derived MLR model is statistically significant, shows very good stability and was used to predict the herbicidal activity of new derivatives having cinnoline, indeno[1.2-c]cinnoline-ll-one, triazolo[1,5-a] pyridine, imidazo[1,2-a]pyridine, triazine and triazolo[1,5-a] pyrimidine scaffolds whose experimental inhibitory activity against D1 PSII had not been determined up to now.

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This work was financially supported by the Project No. 1.1/2016 of the Institute of Chemistry of Romanian Academy, Timişoara. Access to the Chemaxon Ltd., OpenEye Ltd., Accelerys Software Inc. (for the Discovery Studio Visualiser version 2.5 program, used for the preparation of Figs. 1, 2, 3, 4, 5, 8) and Prof. Paola Gramatica from the University of Insubria (Varese, Italy) software are greatly acknowledged by the authors.

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Correspondence to Luminita Crisan.

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Dedicated to the 150th anniversary of the Romanian Academy.

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Funar-Timofei, S., Borota, A. & Crisan, L. Combined molecular docking and QSAR study of fused heterocyclic herbicide inhibitors of D1 protein in photosystem II of plants. Mol Divers 21, 437–454 (2017).

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  • Herbicide
  • Docking
  • Multiple linear regression
  • Omega