Abstract
GPR35, an orphan G protein-coupled receptor, has attracted much attention as a novel therapeutic target for the treatment of diabetes, hypertension, etc. Recently, 8-substituted chromen-4-one-2-carboxylic acid derivatives were identified as potent and selective agonists for human GPR35. In the present study, the three-dimensional quantitative structure–activity relationship (3D-QSAR) models were developed for a series of 8-substituted chromen-4-one-2-carboxylic acid derivatives using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA techniques implemented in the SYBYL software packages. The statistically significant models were obtained with 30 compounds in training set by ligand-based atom-by-atom matching alignment, which were further validated by a test set of eight compounds. The CoMFA model resulted in cross-validated coefficient (q 2) value of 0.610 using 4 components, non-cross-validated coefficient (r 2) value of 0.918 with estimated F value of 69.917, and standard error of estimate (SEE) of 0.352. While the CoMSIA model combined with steric, electrostatic and hydrophobic fields were finally selected (q 2 = 0.646, r 2 = 0.800, F = 53.852, SEE = 0.489, N = 2). For the Topomer CoMFA model, the better statistics were obtained based on fragment units (q 2 = 0.746, r 2 = 0.979, F = 146.294, SEE = 0.175, N = 7). Furthermore, the contour maps obtained from 3D-QSAR studies were appraised for activity trends for the compounds analyzed. The results indicate that steric, electrostatic, and hydrophobic substituents play a significant role in the agonist activity. The data generated from the present study will further help design novel, potent, and selective agonists for GPR35.
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Abbreviations
- 3D-QSAR:
-
Three-dimensional quantitative structure–activity relationship methods
- CoMFA:
-
Comparative molecular field analysis
- CoMSIA:
-
Comparative molecular similarity indices analysis
- GPCRs:
-
G protein-coupled receptors
- GPR35:
-
G protein-coupled receptor 35
- LOO:
-
Leave-one-out procedure
- L5O:
-
Leave-five-out procedure
- N :
-
Optimal number of components
- PLS:
-
Partial least square method
- PRESS:
-
Predictive sum of squares
- q 2 :
-
The cross-validated correlation coefficient
- q 2L5O :
-
Cross-validated correlation coefficient for leave-five-out
- r 2 :
-
Non-cross-validated correlation coefficient
- SEE:
-
Standard error of estimate
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Acknowledgments
The authors would like to acknowledge the financial supports from the National Natural Science Foundation of China (No. 81101687), the “Innovative Drug Development” State Key Science and Technology of China (No. 2009ZX09103-104), Program for the Top Science and Technology Innovation Teams of Higher Learning Institutions of Shanxi Province, and the Technology Innovation Team of Shanxi Province.
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The author declares that there are no conflicts of interest.
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Taigang Liang and Chaoqun Yan have contributed equally to this work.
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Liang, T., Yan, C., Yang, L. et al. 3D-QSAR studies of 8-substituted chromen-4-one-2-carboxylic acid derivatives as potent agonists for the orphan G protein-coupled receptor 35. Med Chem Res 24, 2183–2194 (2015). https://doi.org/10.1007/s00044-014-1287-3
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DOI: https://doi.org/10.1007/s00044-014-1287-3