Li Qinfan, Zhang Lihui, Ma Zhi, Kong Xiangya, Wang Fangfang, Zhang Hong, Wang Yonghua
College of Veterinary Medicine, Northwest A & F University, Yangling 712100, Shaanxi, China; E-Mails:
Int J Mol Sci. 2011;12(9):6293-311. doi: 10.3390/ijms12096293. Epub 2011 Sep 23.
In order to obtain structural features of 3-arylpyrimidin-2,4-diones emerged as promising inhibitors of insect γ-aminobutyric acid (GABA) receptor, a set of ligand-/receptor-based 3D-QSAR models for 60 derivatives are generated using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA). The statistically optimal CoMSIA model is produced with highest q(2) of 0.62, r(2) (ncv) of 0.97, and r(2) (pred) of 0.95. A minor/bulky electronegative hydrophilic polar substituent at the 1-/6-postion of the uracil ring, and bulky substituents at the 3'-, 4'- and 5'-positions of the benzene ring are beneficial for the enhanced potency of the inhibitors as revealed by the obtained 3D-contour maps. Furthermore, homology modeling, molecular dynamics (MD) simulation and molecular docking are also carried out to gain a better understanding of the probable binding modes of these inhibitors, and the results show that residues Ala-183(C), Thr-187(B), Thr-187(D) and Thr-187(E) in the second transmembrane domains of GABA receptor are responsible for the H-bonding interactions with the inhibitor. The good correlation between docking observations and 3D-QSAR analyses further proves the model reasonability in probing the structural features and the binding mode of 3-arylpyrimidin-2,4-dione derivatives within the housefly GABA receptor.
为了获得作为昆虫γ-氨基丁酸（GABA）受体有前景的抑制剂出现的3-芳基嘧啶-2,4-二酮的结构特征，使用比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）生成了一组针对60种衍生物的基于配体/受体的3D-QSAR模型。产生了统计上最优的CoMSIA模型，其最高q(2)为0.62，r(2)（交叉验证）为0.97，r(2)（预测）为0.95。尿嘧啶环1-/6-位的小/大的亲电亲水性极性取代基以及苯环3'-、4'-和5'-位的大取代基有利于增强抑制剂的效力，这由所获得的3D等高线图揭示。此外，还进行了同源建模、分子动力学（MD）模拟和分子对接，以更好地理解这些抑制剂可能的结合模式，结果表明GABA受体第二跨膜结构域中的残基Ala-183(C)、Thr-187(B)、Thr-187(D)和Thr-187(E)负责与抑制剂的氢键相互作用。对接观察结果与3D-QSAR分析之间的良好相关性进一步证明了该模型在探究家蝇GABA受体内3-芳基嘧啶-2,4-二酮衍生物的结构特征和结合模式方面的合理性。
