Discovery of New 2-[(4,6-Dimethoxy-1,3,5-triazin-2-yl)oxy]-6-(substituted phenoxy)benzoic Acids as Flexible Inhibitors of <i>Arabidopsis thaliana</i> Acetohydroxyacid Synthase and Its P197L Mutant

Qu, Ren‐Yu; Yang, Jing‐Fang; Devendar, Ponnam; Kang, Weiming; Liu, Yu‐Chao; Chen, Qiong; Niu, Congwei; Xi, Zhen; Yang, Guang‐Fu

doi:10.1021/acs.jafc.7b05198

Cited by 23 publications

(21 citation statements)

References 45 publications

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“…Our data help to explain why the conservation of this residue is critical for herbicide inhibition, as a mutation will affect the binding of the herbicide and the movement of loop Q. This is consistent with the fact that herbicides that are highly flexible and have a short linker allow favorable interactions with the bulkier leucine side chain of the P197L mutation rather than creating a steric clash and therefore, a high level of resistance (23,24,27).…”

Section: Discussionsupporting

confidence: 80%

Structural insights into the mechanism of inhibition of AHAS by herbicides

Lonhienne

García

Pierens

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Acetohydroxyacid synthase (AHAS), the first enzyme in the branched amino acid biosynthesis pathway, is present only in plants and microorganisms, and it is the target of >50 commercial herbicides. Penoxsulam (PS), which is a highly effective broad-spectrum AHAS-inhibiting herbicide, is used extensively to control weed growth in rice crops. However, the molecular basis for its inhibition of AHAS is poorly understood. This is despite the availability of structural data for all other classes of AHAS-inhibiting herbicides. Here, crystallographic data for AHAS (2.3 Å) and AHAS (2.5 Å) in complex with PS reveal the extraordinary molecular mechanisms that underpin its inhibitory activity. The structures show that inhibition of AHAS by PS triggers expulsion of two molecules of oxygen bound in the active site, releasing them as substrates for an oxygenase side reaction of the enzyme. The structures also show that PS either stabilizes the thiamin diphosphate (ThDP)-peracetate adduct, a product of this oxygenase reaction, or traps within the active site an intact molecule of peracetate in the presence of a degraded form of ThDP: thiamine aminoethenethiol diphosphate. Kinetic analysis shows that PS inhibits AHAS by a combination of events involving FAD oxidation and chemical alteration of ThDP. With the emergence of increasing levels of resistance toward front-line herbicides and the need to optimize the use of arable land, these data suggest strategies for next generation herbicide design.

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Section: Discussionsupporting

confidence: 80%

Structural insights into the mechanism of inhibition of AHAS by herbicides

Lonhienne

García

Pierens

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…The expression of AtAHAS (wild-type and mutant-type) was the same as our previously described method in the literature. 25,[33][34][35] In inhibition kinetic assays, the synthesized compounds were dissolved in DMSO to obtain stock solutions whose concentrations were set at 6, 60, 600, and 6000 μM. In the enzyme reaction system, the solution was diluted to a final concentration of 0.2-200 μM.…”

Section: Enzymatic Kineticsmentioning

confidence: 99%

“…The herbicidal activities of compounds 8-28 against the tested weeds were evaluated according to the method published previously. 25,26,33,34 The results are summarized in Table 2, which was provided by the Zhejiang Research Institute of Chemical Industry (Hangzhou, China).…”

Section: Enzymatic Kineticsmentioning

confidence: 99%

Fragment‐based discovery of flexible inhibitor targeting wild‐type acetohydroxyacid synthase and P197L mutant

Yang

Chen

et al. 2020

Pest Management Science

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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.

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“…Computational models are often used in the development of novel herbicides (Choe et al 2015;Qu et al 2017b;Zhu et al 2011). In a simulation of the evolution of ALS inhibitor resistance associated with the ALS Pro-197-Leu mutation, a series of novel derivatives of 2-benzoyloxy-6-pyrimidinyl salicylic acid were designed and displayed strong inhibitory activity against highly-resistant D. sophia (Qu et al 2017a). However, modeling is only a preliminary tool used to compare the theoretical advantages of management practices.…”

Section: Early Preventative Measuresmentioning

confidence: 99%

Managing herbicide resistance in China

et al. 2020

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Since its initial introduction in the late 1950s, chemical control has dominated weed management practices in China. Not surprisingly, the development of herbicide resistance has become the biggest threat to long-term, sustainable weed management in China. Given that China has followed the same laissez-faire approach towards resistance management that has been practiced in developed countries such as the United State of America, herbicide resistance has rapidly evolved and steadily increased over the years. Previously, we carried out a systematic review to quantitatively assess herbicide resistance issues in China. In this review, our main objective is to focus on mechanistic studies and management practices to document the 1) history of herbicide application in China; 2) resistance mechanisms governing the eight most resistance-prone herbicide groups, including acetolactate synthase inhibitors, acetylCoA carboxylase inhibitors, synthetic auxin herbicides, 5-enolpyruvylshikimate-3-phosphate synthase inhibitors, protoporphyrinogen oxidase inhibitors, photosystem I electron diverters, photosystem II inhibitors, and long-chain fatty-acid inhibitors; and 3) herbicide resistance management strategies commonly used in China, including chemical, cultural, biological, physical, and integrated approaches. At the end, perspectives and future research are discussed to address the pressing need for the development of integrated herbicide resistance management in China.

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Discovery of New 2-[(4,6-Dimethoxy-1,3,5-triazin-2-yl)oxy]-6-(substituted phenoxy)benzoic Acids as Flexible Inhibitors of Arabidopsis thaliana Acetohydroxyacid Synthase and Its P197L Mutant

Cited by 23 publications

References 45 publications

Structural insights into the mechanism of inhibition of AHAS by herbicides

Structural insights into the mechanism of inhibition of AHAS by herbicides

Fragment‐based discovery of flexible inhibitor targeting wild‐type acetohydroxyacid synthase and P197L mutant

Managing herbicide resistance in China

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