2. Academic Validation
  3. Discovery of novel inhibitors targeting the PH domain of PcORP1: Virtual screening, structural optimization, biological evaluation

Discovery of novel inhibitors targeting the PH domain of PcORP1: Virtual screening, structural optimization, biological evaluation

  • Eur J Med Chem. 2025 Oct 15:296:117900. doi: 10.1016/j.ejmech.2025.117900.
Xingxing Lu 1,  Xiaofei Liu 2,  Yu Sun 3,  Changkai Wang 3,  Xiaoming Zhang 3,  Xinling Yang 3,  Yun Ling 3,  Jianqiang Miao 4,  Zhongqiao Huang 5,  Li Zhang 6,  Xili Liu 7
Affiliations

Affiliations

  • 1 State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, College of Plant Protection, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, China; Innovation Center of Pesticide Research Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, 100193, China.
  • 2 State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, College of Plant Protection, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, China; Department of Plant Pathology, College of Plant Protection, China Agricultural University, Beijing, 100193, China.
  • 3 Innovation Center of Pesticide Research Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, 100193, China.
  • 4 State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, College of Plant Protection, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, China; Shaanxi Meibang Pharmaceutical Group Co. Ltd., Weinan, 715500, China.
  • 5 Department of Plant Pathology, College of Plant Protection, China Agricultural University, Beijing, 100193, China.
  • 6 Innovation Center of Pesticide Research Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, 100193, China. Electronic address: zhang_li@cau.edu.cn.
  • 7 State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, College of Plant Protection, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, China; Department of Plant Pathology, College of Plant Protection, China Agricultural University, Beijing, 100193, China. Electronic address: seedling@nwafu.edu.cn.
PMID: 40561646 DOI: 10.1016/j.ejmech.2025.117900
Abstract

The oxysterol-binding protein (OSBP)-related protein 1 (ORP1) serves as a critical target for oomycete inhibitors, given that OSBPI fungicides demonstrate exceptionally high biological efficacy through their specific binding to the ORD domain of ORP1. Our previous research has demonstrated that the PH domain of ORP1 in Phytophthora species plays a crucial role in its biological functions. However, the potential of this domain as a viable target for fungicides remains to be elucidated. In this study, we describe the discovery of the PH domain inhibitor, compound X4. Initially, a hit compound VS-07, with good fungicidal activity against oomycetes, was identified through docking-based virtual screening. Subsequently, 27 analogs were designed and synthesized by structurally optimizing of VS-07. Among these, compound X4 demonstrated exceptional inhibitory activities against six oomycetes, with EC50 values ranging from 1 to 4 μg/mL, and effectively inhibited the PH domain of PcORP1. Molecular docking revealed that compound X4 formed more hydrogen bond interactions with Trp51, Ser91, and Thr93 of the PH domain. Preliminary mechanistic studies indicated that compound X4 affected lipid transport and metabolism by targeting the PH domain of PcORP1, resulting in mycelium hyperplasia and cell membrane ruffling in P. capsici. Moreover, compound X4 provided over 90 % protection against P. capsici in detached leaf assays at 100 and 200 μg/mL. This study not only validates the targetability of the PH domain of ORP1, but also identifies compound X4 as a potential inhibitor targeting this domain, offering a potential fungicide for oomycete management.

Keywords

Docking-based virtual screening; Fungicidal mechanism; PH domain of ORP1; Phytophthora capsici.

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