Weed Research Laboratory, Nanjing Agricultural University, Nanjing 210095, China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
J Adv Res. 2022 Sep;40:29-44. doi: 10.1016/j.jare.2021.12.001. Epub 2021 Dec 14.
Computer-aided design has become an important tool to develop novel pesticides based on natural lead compounds. Tenuazonic acid (TeA), a typical representative of the natural tetramic acid family, was patented as a potential bioherbicide. However, its herbicidal efficacy is still not up to the ideal standard of commercial products.
We aim to find new TeA's derivatives with improved potency.
Molecular docking was used to build ligand-acceptor interaction models, design and screen new derivatives. Phytotoxicity, oxygen evolution rate, chlorophyll fluorescence and herbicidal efficacy were determined to estimate biological activity of compounds.
With the aid of a constructed molecular model of natural lead molecule TeA binding to the Q site in Arabidopsis D1 protein, a series of derivatives differing in the alkyl side chain were designed and ranked according to free energies. All compounds are stabilized by hydrogen bonding interactions between their carbonyl oxygen O2 and D1-Gly256 residue; moreover, hydrogen bond distance is the most important factor for maintaining high binding affinity. Among 54 newly designed derivatives, D6, D13 and D27 with better affinities than TeA were screened out and synthesized to evaluate their photosynthetic inhibitory activity and herbicidal efficacy. Analysis of structure-activity relationship indicated that D6 and D13 with sec-pentyl and sec-hexyl side chains, respectively, were about twice more inhibitory of PSII activity and effective as herbicide than TeA with a sec-butyl side chain.
D6 and D13 are promising compounds to develop TeA-derived novel PSII herbicides with superior performance.
计算机辅助设计已成为基于天然先导化合物开发新型农药的重要工具。涕灭威酸（TeA）是天然四氢酸家族的典型代表，已被专利为有潜力的生物除草剂。然而，其除草效果仍未达到商业产品的理想标准。
我们旨在寻找具有更高活性的新型 TeA 衍生物。
采用分子对接方法构建配体-受体相互作用模型，设计并筛选新的衍生物。通过测定化合物的生物活性，如植物毒性、氧释放率、叶绿素荧光和除草效果来评估。
借助天然先导分子 TeA 与拟南芥 D1 蛋白 Q 位点结合的分子模型，设计并根据自由能对一系列烷基侧链不同的衍生物进行了排序。所有化合物均通过羰基氧 O2 与 D1-Gly256 残基之间的氢键相互作用稳定；此外，氢键距离是保持高结合亲和力的最重要因素。在所设计的 54 个衍生物中，筛选出与 TeA 相比具有更好亲和力的 D6、D13 和 D27，并进行了合成以评估其对光合作用的抑制活性和除草效果。结构-活性关系分析表明，具有仲戊基和仲己基侧链的 D6 和 D13 对 PSII 活性的抑制作用约为 TeA 的两倍，且作为除草剂的效果优于具有仲丁基侧链的 TeA。
D6 和 D13 是开发具有优异性能的 TeA 衍生新型 PSII 除草剂的有前途的化合物。
