Structure-Based Design, Virtual Screening, and Discovery of Novel Patulin Derivatives as Biogenic Photosystem II Inhibiting Herbicides

Abstract

Computer-aided design usually gives inspirations and has become a vital strategy to develop novel pesticides through reconstructing natural lead compounds. Patulin, an unsaturated heterocyclic lactone mycotoxin, is a new natural PSII inhibitor and shows significant herbicidal activity to various weeds. However, some evidence, especially the health concern, prevents it from developing as a bioherbicide. In this work, molecular docking and toxicity risk prediction are combined to construct interaction models between the ligand and acceptor, and design and screen novel derivatives. Based on the analysis of a constructed patulin-Arabidopsis D1 protein docking model, in total, 81 derivatives are designed and ranked according to quantitative estimates of drug-likeness (QED) values and free energies. Among the newly designed derivatives, forty-five derivatives with better affinities than patulin are screened to further evaluate their toxicology. Finally, it is indicated that four patulin derivatives, D3, D6, D34, and D67, with higher binding affinity but lower toxicity than patulin have a great potential to develop as new herbicides with improved potency.

Keywords: D1 protein; docking; homology modeling; natural product; photosynthetic inhibitor.

Figure 1

Flow chart illustrating the structure-based ligand design and discovery of novel patulin derivatives with high herbicidal activity.

Figure 2

Simulated modeling of patulin binding to the D1 protein of Arabidopsis. (A) The chemical structure of patulin. (B) Hydrogen bonding interactions of patulin binding to the D1 protein. (C) The stereo view of the patulin binding environment of the D1 protein, in which carbon, oxygen, nitrogen, and hydrogen atoms are displayed in gray, red, blue, and white, respectively. The green dashed lines represent the possible hydrogen bonds. (D) The surface representation of the Q_B binding site with bound patulin.

Figure 3

Binding interactions of patulin derivatives at the Q_B binding site of D1 protein of Arabidopsis. An illustration of the binding mode of compounds D3 (A), D6 (D), D34 (G), and D67 (J) binding to the D1 protein, respectively. Key interaction types are represented in the color code. The stereo view of compound D3 (B), D6 (E), D34 (H), and D67 (K) binding environments at the Q_B binding site. The surface representation of the Q_B binding site with compounds D3 (C), D6 (F), D34 (I), and D67 (L), respectively.