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1、基于 CoMFA，CoMSIA 和 DFT 计算的乙酰羟基酸合成酶制剂嘧 啶水杨酸类化合物构效关系研究 基于 CoMFA，CoMSIA 和 DFT 计算的乙酰羟基酸合成酶制剂嘧 啶水杨酸类化合物构效关系研究 何彦祯，张 莉，李元祥，万 坚，杨光富何彦祯，张 莉，李元祥，万 坚，杨光富 农药与化学生物学教育部重点实验室，华中师范大学化学学院，武汉，430079 E-mail: gfyang 乙酰羟基酸合成酶(AHAS；又称乙酰乳酸合成酶，ALS；EC 2.2.1.6)是催化支链氨基酸缬缬氨酸、 亮氨酸和异亮氨酸生物合成第一步的合成酶 1。它已经确定为五大除草剂的作用靶标：磺酰脲类化合 物 (su
2、lfonylureas) ， 咪 唑 啉 酮 类 化 合 物 (imidazolinones) ， 三 唑 并 嘧 啶 类 化 合 物 (triazolopyrimidines)，嘧啶(氧)硫苯甲酸酯类化合物 (pyrimidinylthiobenzoates)和磺酰胺羰 基三唑啉酮类化合物(sulfonylaminocarbonyltriazolinones)。由于AHAS抑制剂普遍具有对哺乳动 物低毒，高选择性，超高效等现代农药所需的重要特征，从而使AHAS抑制剂得到高速发展且一直受 到广泛关注。其中二甲氧基嘧啶(硫代)水杨酸属于嘧啶(氧)硫苯甲酸酯类抑制剂 2。 活性构象的选取及原子的电
3、荷分布在 3D-QSAR分析中起着非常关键的作用，本研究所有化合物采 用Gaussian03 软件包 3进行计算，选取密度泛函理论（DFT）的B3LYP4,5方法在 631G*基组6下进行结 构优化和布居分析。选择Merz-Singh-Kollman（MK） 7,8方法分析化合物的静电势分布，得到静电势 拟合 （ESP） 的电荷。 采用Sybyl7.0 软件中的比较分子力场(CoMFA) 9和相似性比较分子力场(CoMSIA)10 对一系列O-(4,6-二甲氧基嘧啶-2-基)水杨酸及其硫代物在基于DFT方法优化后的稳定构象的基础上 建立 3D-QSAR模型， 模型具有较高的可靠性和预测能力(C
4、oMFA r 2=0.960, q2=0.788； CoMSIA r2=0.921, q 2=0.720)，同时对训练集化合物也有很好的预测能力(CoMFA r2 pred=0.836；CoMSIA r 2 pred=0.879)。训 练集和测试集中化合物的实验和观测值的比较图见Fig.1， 并且将得到的力场系数曲面图投影到蛋白 质晶体结构的结合腔中，其立体场、静电场和疏水场与对接结果假设的结合模型非常匹配。 A B Fig.1 A. CoMFA predicted versus experimental pI50 values. B. CoMSIA based on steric, elec
5、trostatic and hydrophobic fields predicted versus experimental pI50 values. Open circles represent predictions for the training set; solid triangles represent predictions for test set. 关键词：乙酰羟基酸合成酶抑制剂，3D-QSAR，DFT，CoMFA，CoMSIA 参考文献： 1 Duggleby, R. G. ; Pang, S. S. Journal of Biochemistry and Molecula
6、r Biology, 2000, 33(1): 136. 2 Nezu, Y.; Wada, N.; Saitoh, Y.; Takahashi, S. Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, Jr., T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.
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8、azyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K. G.; Voth, A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui
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13、ionships of Pyrimidinyl Salicylic Acids as Acetohydroxyacid Synthase Inhibitors by Molecular Docking, CoMFA, CoMSIA, and DFT Calculation Yan-Zhen He, Li Zhang, Yuan-Xiang Li, Jian Wan, Guang-Fu Yang * Abstract: Acetohydroxyacid synthase (AHAS ， EC 2.2.1.6) catalyzes the first common step in branched
14、-chain amino acid biosynthesis. The enzyme is inhibited by several chemical classes of compounds and this inhibition is the basis of action of the dimethoxypyrimidinyl(thio)salicylic acids which belong to pyrimidinylthiobenzoates herbicides. Here we developed three-dimensional quantitative structure
15、-activity relationships (3D-QSAR) of a series of O-(4,6-dimethoxypyrimidin-2-yl)salicylic acids and their thio analogs by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on the quantum chemical calculations at the DFT/B3LYP leve
16、l of theory. The present work had proved that the DFT-based optimized conformations could lead to better 3D-QSAR model with good predictive power (CoMFA r2=0.960, q2=0.788; CoMSIA r2=0.921, q2=0.720). The resulting fields were mapped on the published crystal structure of the yeast enzyme and it was shown that the steric, electrostatic and hydrophobic fields are in good agreement with the proposed dimethoxypyrimidinylsalicylic acid-AHAS int
