Fragment-based discovery of flexible inhibitor targeting wild-type acetohydroxyacid synthase and P197L mutant
Fragment-based discovery of flexible inhibitor targeting wild-type acetohydroxyacid synthase and P197L mutant
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基于片段的针对野生型乙酰羟酸合酶和 P197L 突变体的灵活抑制剂的发现
DOI：
10.1002/ps.5739
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发表时间：
2020-01-25
影响因子：
4.1
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
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作者：
Qu, Ren-Yu;Yang, Jing-Fang;Yang, Guang-Fu
杂草抗性的增强对现有乙酰羟基酸合成酶（AHAS）抑制除草剂的使用提出了挑战。因此，目前迫切需要发现一种新的AHAS抑制剂，以有效控制靶点突变产生的AHAS除草剂抗性杂草。结果为了对抗P197L突变的AHAS对杂草的抗性，我们建立了一个由嘧啶水杨酸衍生物组成的结构文库。利用药物载体连接片段虚拟筛选（PFVS）方法，鉴定了含有6-苯氧甲基取代基的hit化合物8为具有抗耐药性的潜在AHAS抑制剂。随后，合成了化合物8的衍生物并对其抑菌活性进行了评价。基于酶的结构-活性关系和结构-抗性关系研究的研究导致了一个合格的候选人的发现，28。该化合物不仅能显著抑制野生型拟南芥（At） AHAS和P197L突变体的活性，而且具有良好的抗抗性（RF = 0.79）。值得注意的是，与双嘧菌酯37.5 ~ 150 g /公顷（g a.i. ha(-1)）的有效成分浓度相比，化合物27对敏感和抗性的索非蒿（Descurainia sophia）均表现出更高的生长抑制作用。结论该化合物具有很大的开发潜力，可作为有效防治含有P197L突变的AHAS的抗除草剂杂草的新线索。此外，我们的研究为使用基于片段的药物设计方法发现新的，有效的和抗耐药性抑制剂提供了积极的案例。(c) 2020年化学工业学会
BACKGROUND Intensifying weed resistance has challenged the use of existing acetohydroxyacid synthase (AHAS)-inhibiting herbicides. Hence, there is currently an urgent requirement for the discovery of a new AHAS inhibitor to effectively control AHAS herbicide-resistant weed species produced by target mutation. RESULTS To combat weed resistance caused by AHAS with P197L mutation, we built a structure library consisting of pyrimidinyl-salicylic acid derivatives. Using the pharmacophore-linked fragment virtual screening (PFVS) approach, hit compound 8 bearing 6-phenoxymethyl substituent was identified as a potential AHAS inhibitor with antiresistance effect. Subsequently, derivatives of compound 8 were synthesized and evaluated for their inhibitory activities. The study of the enzyme-based structure-activity relationship and structure-resistance relationship studies led to the discovery of a qualified candidate, 28. This compound not only significantly inhibited the activity of wild-type Arabidopsis thaliana (At) AHAS and P197L mutant, but also exhibited good antiresistance properties (RF = 0.79). Notably, compared with bispyribac at 37.5-150 g of active ingredient per hectare (g a.i. ha(-1)), compound 27 exhibited higher growth inhibition against both sensitive and resistant Descurainia sophia, CONCLUSION The title compounds have great potential to be developed as new leads to effectively control herbicide-resistant weeds comprising AHAS with P197L mutation. Also, our study provided a positive case for discovering novel, potent and antiresistance inhibitors using a fragment-based drug design approach. (c) 2020 Society of Chemical Industry