2. Academic Validation
  3. A first-in-class dimethyl 2-acetamido terephthalate inhibitor targeting Conyza canadensis SHMT1 with a novel herbicidal mode-of-action

A first-in-class dimethyl 2-acetamido terephthalate inhibitor targeting Conyza canadensis SHMT1 with a novel herbicidal mode-of-action

  • J Adv Res. 2024 Aug:62:59-70. doi: 10.1016/j.jare.2023.10.003.
Dingfeng Luo 1,  Zhendong Bai 2,  Haodong Bai 2,  Na Liu 1,  Jincai Han 1,  Changsheng Ma 1,  Di Wu 2,  Lianyang Bai 3,  Zuren Li 4
Affiliations

Affiliations

  • 1 Hunan Provincial Key Laboratory for Biology and Control of Weeds, Hunan Academy of Agricultural Sciences, Changsha 410125, China; Longping Branch, College of Biology, Hunan University, Changsha 410125, China.
  • 2 Hunan Provincial Key Laboratory for Biology and Control of Weeds, Hunan Academy of Agricultural Sciences, Changsha 410125, China.
  • 3 Hunan Provincial Key Laboratory for Biology and Control of Weeds, Hunan Academy of Agricultural Sciences, Changsha 410125, China; Longping Branch, College of Biology, Hunan University, Changsha 410125, China. Electronic address: lybai@hunaas.cn.
  • 4 Hunan Provincial Key Laboratory for Biology and Control of Weeds, Hunan Academy of Agricultural Sciences, Changsha 410125, China; Longping Branch, College of Biology, Hunan University, Changsha 410125, China. Electronic address: lizuren88214@hunaas.cn.
PMID: 37820886 DOI: 10.1016/j.jare.2023.10.003
Abstract

Introduction: Herbicide application is a highly efficiency method of weed control that boots agricultural output and assures food security. The development of novel herbicides focuses on improved bioactivity and new modes of action. The amino acid biosynthesis was validated as a promising novel mode of action for herbicidal compounds. However, the amino acid biosynthesis Enzyme remains largely unexplored for herbicidal targets.

Objectives: Serine hydroxymethyl transferase (SHMT) is an essentialenzyme in the photorespiratory cycle. The study aims to explore Conyza canadensis SHMT1 (CcSHMT1) as a promising target for herbicide discovery.

Methods: Structure determination of CcSHMT1 was resolved by X-ray crystallography. Virtual screening docking experiments were performed with Glide version 5.5. Novel derivatives of dimethyl 2-acetamido terephthalate were further designed, synthesized, and bioassay. The druggability of the inhibitor was evidenced by ultrastructural changes in mitochondria, in vivo and vitro Enzyme activity assays, and genetics analysis.

Results: CcSHMT1 has a typical PLP-dependent Enzyme 3D structure. The dimethyl 2-acetamido terephthalate-containing compounds had herbicidal activity. Dimethyl 2-(2-(4-(2-(4-bromo-2-chlorophenoxy) acetyl)piperazin-1-yl)acetamido) terephthalate (Compound 9ay, EC50 = 193.8 g a.i./ ha) exhibited the highest herbicidal activity on tested weed among the synthesized compounds. Compound 9ay had no obvious adverse effect on the growth of maize and honeybees. Compound 9ay was verified to target CcSHMT1 as an herbicide candidate.

Conclusion: A first-in-class CcSHMT1 inhibitor that could be developed as a potent herbicide with a new mode of action and provide an avenue for discovering novel inhibitors of pyridoxal-5-phosphate-dependent Enzymes.

Keywords

Crystal structure; Herbicide target; In silico screening; Serine hydroxymethyltransferase (SHMT); Synthesis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162883
    SHMT1 Inhibitor