Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method
Abstract
:1. Introduction
2. Results and Discussion
2.1. Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) Statistical Results
PLS Statistics | CoMFA | CoMSIA |
---|---|---|
Q2 | 0.372 | 0.509 |
R2ncv | 0.896 | 0.841 |
SEE | 0.235 | 0.288 |
F | 138.780 | 100.745 |
R2pred | 0.544 | 0.745 |
SEP | 0.576 | 0.507 |
OPN | 7 | 6 |
Contribution (%) | ||
Steric | 54.8 | 14.8 |
Electrostatic | 45.2 | – |
Hydrophobic | – | 39.0 |
H-bond donor | – | 23.1 |
H-bond acceptor | – | 23.1 |
2.2. Comparative Molecular Similarity Index Analysis (CoMSIA) Contour Maps Analysis
2.3. Docking Study
2.4. Molecular Dynamics (MD) Analysis
2.4.1. Receptor in Water
2.4.2. Receptor in Lipid Bilayer
2.5. Docking Comparison
No. | Researchers | Template | Binding Site | Binding Interactions | Crucial Residues |
---|---|---|---|---|---|
1 | Clark et al. [42] | Bovine rhodopsin | P1 | Ionic interaction, H-bond, hydrophobic effect | Asp123, Gln276 |
2 | Tavares et al. [38] | Bovine rhodopsin | P1 | Ionic interaction, H-bond | Asp123, Tyr273 |
3 | Witty et al. [46] | Bovine rhodopsin | P1 | Unclear | Asp123 |
4 | Giordanetto et al. [47] | 1U19 a | P1 | Ionic interaction, H-bond | Asp123, Gln127 |
5 | Cavasatto et al. [48] | 1L9H a | P1 | π–π stacking, H-bond | Asp123, Gln127 Trp269, Ile297, Gly300, Tyr301 |
6 | Abu-Hammad et al. [49] | 1U19 a | P2 | Van der Waals stacking, H-bond, hydrophobic effect | Gln212, Gln276 Phe187 |
7 | Sasmal et al. [50] | 2RH1 a, 2VT4 a | P1 | Ionic interaction, H-bond, hydrophobic effect | Asp123, Gln127, Gln212, Gln268, Asn255 |
8 | Ulven et al. [32] | 1F88 a | P1 | Ionic interaction, H-bond, hydrophobic effect | Asp123, Gln212 |
9 | Sasmal et al. [29] | 2RH1 a | P1 | Ionic interaction, H-bond | Asp123, Gln127, Gln212, Gln276, Thr164 |
10 | Helal et al. [39] | 1U19 a | P1 | Ionic interaction, H-bond, hydrophobic effect | Asp123, Gln127, Gln212, Gln276, Trp179, Thr131 |
11 | Cirauqui et al. [43] | 1U19 a | P1 | Ionic interaction, H-bond, hydrophobic effect | Asp123, Gln212, Gln276,Tyr273, Thr131 |
12 | Kamata et al. [51] | 1F88 a | P1 | H-bond, hydrophobic effect | Gln127, Asn294 |
3. Experimental Section
3.1. Biological Activities and Dataset Construction
3.2. Conformational Optimization and Alignment
3.3. Comparative Molecular Field Analysis (CoMFA) and CoMSIA Studies
3.4. Partial Least Squares (PLS) Analysis and Validation of Quantitative Structure–Activity (QSAR) Models
3.5. Homology Modeling
3.6. Docking Simulations
3.7. MD Simulations
4. Conclusions
- (1)
- The most potent Compound 169 fits into the conventional binding pocket P1 and follows the binding mode of Mode I with the ligand owning a central basic nitrogen taking an approximately linear configuration.
- (2)
- Two hydrophobic subsites S1 and S2 are observed to compose P1 of MCHR1.
- (3)
- Antagonist 169 forms a conventional interaction of salt bridge with Asp123 and six H-bonds with Gln127, Gln212, Gln276, Tyr272, Trp179 and Ile100. To the best of our knowledge, this is the first time the role of Tyr272 and Ile100 in hydrogen bonds is noticed in the ligand–MCHR1 complex.
- (4)
- In general, a salt bridge with Asp123, several H-bonds with glutamine and at least one hydrophobic pocket are usually involved in the binding of MCHR1 antagonists.
- (5)
- MD analysis processed within a lipid bilayer environment shows similar results to those performed in water.
Supplementary Materials
Supplementary Files
Supplementary File 1Acknowledgments
Author Contributions
Conflicts of Interest
References
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Wu, M.; Li, Y.; Fu, X.; Wang, J.; Zhang, S.; Yang, L. Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method. Int. J. Mol. Sci. 2014, 15, 15475-15502. https://doi.org/10.3390/ijms150915475
Wu M, Li Y, Fu X, Wang J, Zhang S, Yang L. Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method. International Journal of Molecular Sciences. 2014; 15(9):15475-15502. https://doi.org/10.3390/ijms150915475
Chicago/Turabian StyleWu, Mingwei, Yan Li, Xinmei Fu, Jinghui Wang, Shuwei Zhang, and Ling Yang. 2014. "Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method" International Journal of Molecular Sciences 15, no. 9: 15475-15502. https://doi.org/10.3390/ijms150915475