期刊
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
卷 169, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.pestbp.2020.104673
关键词
Oxysterol binding protein; Oxathiapiprolin; Resistance; Molecular design
资金
- National Key Research and Development Program of China [2017YFD0200506]
- National Natural Science Foundation of China [21977035, 21772057]
- Program of Introducing Talents of Discipline to Universities of China (111 program) [B17019]
Oxathiapiprolin, the first successful oxysterol binding protein (OSBP) inhibitor for oomycete control, is regarded as an important milestone in the history of fungicide discovery. However, its interaction with OSBP remain unclear. Moreover, some plant pathogenic oomycetes have developed medium to high resistance to oxathiapiprolin. In this paper, the three-dimensional (3D) structure of OSBP from Phytophthora capsici (pcOSBP) was built, and its interaction with oxathiapiprolin was systematically investigated by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. The computational results showed that oxathiapiprolin bound to pcOSBP forms H-bonds with Leu73, Lys74, Ser69, and water molecules. Then, based on its interaction with pcOSBP, oxathiapiprolin was structurally modified to discover new analogs with high fungicidal activity and a low risk of resistance. Fortunately, compound 1e was successfully designed and synthesized as the most potent candidate, and it showed a much lower resistance risk (RF < 1) against LP3-M and LP3-H in P. capsici. The present work indicated that the piperidinyl-thiazole-isoxazoline moiety is useful for further optimization. Furthermore, compound 1e could be used as a lead compound for the discovery of new OSBP inhibitors.
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