Int. J. Mol. Sci. 2011, 12(9), 6293-6311; doi:10.3390/ijms12096293
Article

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

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Received: 1 August 2011; in revised form: 26 August 2011 / Accepted: 13 September 2011 / Published: 23 September 2011
(This article belongs to the Section Molecular Recognition)
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Abstract: 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, r2ncv of 0.97, and r2pred 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.
Keywords: 3-arylpyrimidin-2,4-diones; GABA receptor; 3D-QSAR; homology modeling; molecular dynamics simulation; molecular docking
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Li, Q.; Zhang, L.; Ma, Z.; Kong, X.; Wang, F.; Zhang, H.; Wang, Y. Probing Structural Features and Binding Mode of 3-Arylpyrimidin-2,4-diones within Housefly γ-Aminobutyric Acid (GABA) Receptor. Int. J. Mol. Sci. 2011, 12, 6293-6311.

AMA Style

Li Q, Zhang L, Ma Z, Kong X, Wang F, Zhang H, Wang Y. Probing Structural Features and Binding Mode of 3-Arylpyrimidin-2,4-diones within Housefly γ-Aminobutyric Acid (GABA) Receptor. International Journal of Molecular Sciences. 2011; 12(9):6293-6311.

Chicago/Turabian Style

Li, Qinfan; Zhang, Lihui; Ma, Zhi; Kong, Xiangya; Wang, Fangfang; Zhang, Hong; Wang, Yonghua. 2011. "Probing Structural Features and Binding Mode of 3-Arylpyrimidin-2,4-diones within Housefly γ-Aminobutyric Acid (GABA) Receptor." Int. J. Mol. Sci. 12, no. 9: 6293-6311.


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