Probing Structural Features and Binding Mode of 3-Arylpyrimidin-2,4-diones within Housefly γ-Aminobutyric Acid (GABA) Receptor

International Journal of Molecular Sciences

Qinfan Li¹  Lihui Zhang¹  Zhi Ma²  Xiangya Kong¹  Fangfang Wang²  Hong Zhang² 

[1] College of Veterinary Medicine, Northwest A & F University, Yangling 712100, Shaanxi, China; E-Mails:;College of Life Science, Northwest A & F University, Yangling 712100, Shaanxi, China; E-Mails:

关键词: 3-arylpyrimidin-2;    4-diones;    GABA receptor;    3D-QSAR;    homology modeling;    molecular dynamics simulation;    molecular docking;   

DOI  :  10.3390/ijms12096293

来源: mdpi

【 摘 要 】

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 q² of 0.62, r²_ncv of 0.97, and r²_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.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.