Computational Analysis of Structure-Based Interactions for Novel H1-Antihistamines
"> Figure 1
<p>Distribution of activities (p<span class="html-italic">K<sub>i</sub></span>) for the training and the test sets <span class="html-italic">versus</span> the numbers of compounds. The training and the test sets are colored blue and orange, respectively.</p> "> Figure 2
<p>The ligand-based correlation plots of the predicted <span class="html-italic">versus</span> the actual p<span class="html-italic">K<sub>i</sub></span> values using the training (filled red triangles) and the test (filled black dots) set compounds based on the optimal CoMSIA model.</p> "> Figure 3
<p>Contour maps of CoMSIA combined with compound 49. (<b>A</b>) Contour maps in steric (green/yellow) fields. Green and yellow contours represent regions where bulky groups will increase and decrease the activity, respectively; (<b>B</b>) Contour maps in electrostatic (red/blue) fields. Red and blue contours represent regions where negative- and positive-charged substituents will decrease and increase the activity, respectively; (<b>C</b>) Contour maps in hydrophobic (yellow/gray) fields. Yellow and gray contours represent regions where the hydrophobic and hydrophilic groups will increase their activity; (<b>D</b>) Contour maps in H-bond (HB) donor (cyan/purple) fields. Cyan and purple contours represent regions where HB donor substituents will enhance and decrease the activity, respectively.</p> "> Figure 4
<p>(<b>A</b>) Binding poses of co-crystallized (magenta) and re-docked (green) compound doxepin; (<b>B</b>) overlap of the compound 49 (orange) and experimental doxepin (green; PDB code: 3RZE) conformation.</p> "> Figure 5
<p>Docked conformation of compound 49 into histamine H<sub>1</sub> receptor. The projection highlights the structure of the active site with compound 49, which is displayed in sticks.</p> "> Figure 6
<p>(<b>A</b>) Plot of the root-mean-square deviation (RMSD) of docked complex/ligand <span class="html-italic">versus</span> the MD simulation time in the MD-simulated structures; (<b>B</b>) view of the superimposed backbone atoms of the average structure for the MD simulations and the initial structure of the docking for the complex. Compound 49 is represented as a carbon-chain in green for the initial complex and a carbon-chain in orange for the average structure, respectively.</p> "> Figure 7
<p>Plot of the MD-simulated structures of the binding site with compound 49. H-bonds are shown as dotted black lines; amino acid residues in the active site are represented as sticks.</p> "> Figure 8
<p>(<b>A</b>) Compound 49 used as the template molecule for alignments, with the common framework marked in blue bold. The substituent containing a protonated –NMe<sub>2</sub> group at the position-18 is depicted in a red oval, which would be more desirable for potent antagonism activity; (<b>B</b>–<b>D</b>) show the results of Alignment-I, -II and -III of all molecules, respectively. All compounds in these panels are colored white for common carbon, blue for nitrogen, red for oxygen, yellow for sulfur and cyan for hydrogen atoms, respectively.</p> "> Figure 9
<p>Proposed hypothetical histamine H<sub>1</sub>-receptor active site models. The structure-activity relationship is taken from the results of 3D-QSAR, docking and MD simulation studies for compound 49.</p> ">
Abstract
:1. Introduction
2. Results
2.1. 3D-QSAR Analysis
PLS Statistics | N | Q2 | SEP | R2ncv | SEE | F | R2pred | Contribution (%) | ||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
S | E | H | D | A | ||||||||
CoMFA | ||||||||||||
S | 1 | 0.013 | 0.730 | 0.214 | 0.652 | 25.618 | 0.020 | 100 | – | – | – | – |
E | 1 | −0.081 | 0.764 | 0.088 | 0.702 | 9.052 | 0.204 | – | 100 | – | – | – |
SE | 4 | 0.044 | 0.730 | 0.563 | 0.494 | 29.325 | 0.064 | 50.2 | 49.8 | – | – | – |
CoMSIA | ||||||||||||
S | 1 | −0.223 | 0.628 | 0.213 | 0.504 | 8.365 | 0.272 | 100 | – | – | – | – |
E | 4 | 0.224 | 0.659 | 0.601 | 0.472 | 34.296 | 0.450 | – | 100 | – | – | – |
H | 5 | 0.132 | 0.700 | 0.581 | 0.487 | 24.921 | 0.177 | – | – | 100 | – | – |
D | 4 | 0.126 | 0.698 | 0.164 | 0.683 | 4.450 | 0.075 | – | – | – | 100 | – |
A | 3 | −0.011 | 0.747 | 0.271 | 0.634 | 11.389 | 0.005 | – | – | – | – | 100 |
SE | 5 | 0.196 | 0.680 | 0.661 | 0.437 | 35.113 | 0.503 | 20.5 | 79.5 | – | – | – |
SH | 7 | 0.116 | 0.714 | 0.734 | 0.392 | 34.635 | – | 27.5 | – | 72.5 | – | – |
SD | 4 | 0.212 | 0.663 | 0.366 | 0.595 | 13.116 | −0.07 | 36.8 | – | – | 63.2 | – |
SA | 3 | −0.01 | 0.743 | 0.329 | 0.608 | 15.057 | −0.022 | 27.4 | – | – | – | 72.6 |
EH | 4 | 0.297 | 0.501 | 0.913 | 0.177 | 73.179 | 0.920 | – | 66.7 | 33.3 | – | – |
ED | 2 | 0.197 | 0.518 | 0.583 | 0.373 | 21.010 | – | – | 75.2 | – | 24.8 | – |
EA | 5 | 0.255 | 0.525 | 0.906 | 0.187 | 51.889 | 0.913 | – | 56.8 | – | – | 43.2 |
HD | 6 | 0.044 | 0.606 | 0.771 | 0.297 | 14.615 | 0.789 | – | – | 89.6 | 10.4 | – |
HA | 3 | 0.226 | 0.517 | 0.802 | 0.261 | 39.174 | – | – | – | 33.6 | – | 66.4 |
DA | 2 | 0.186 | 0.521 | 0.642 | 0.346 | 26.847 | 0.670 | – | – | – | 27.5 | 72.5 |
SEH | 5 | 0.260 | 0.524 | 0.936 | 0.154 | 78.990 | 0.940 | 10.8 | 60.0 | 29.2 | – | – |
SED | 2 | 0.143 | 0.535 | 0.597 | 0.366 | 22.240 | 0.628 | 11.2 | 65.6 | – | 23.2 | – |
SEA | 5 | 0.261 | 0.523 | 0.908 | 0.185 | 53.165 | 0.915 | 11.3 | 50.5 | – | – | 38.2 |
SHD | 6 | −0.115 | 0.655 | 0.819 | 0.264 | 19.552 | 0.832 | 28.2 | – | 59.9 | 11.9 | – |
SHA | 2 | 0.169 | 0.526 | 0.675 | 0.329 | 31.120 | 0.699 | 11.1 | – | 23.8 | – | 65.1 |
SDA | 2 | 0.149 | 0.533 | 0.655 | 0.339 | 28.530 | 0.682 | 10.5 | – | – | 25.1 | 64.4 |
EHD | 6 | 0.223 | 0.547 | 0.939 | 0.154 | 66.188 | 0.943 | – | 60.0 | 30.5 | 9.4 | – |
EHA | 4 | 0.284 | 0.506 | 0.905 | 0.184 | 66.697 | 0.913 | – | 43.3 | 21.8 | – | 35.0 |
EDA | 3 | 0.206 | 0.523 | 0.831 | 0.242 | 47.381 | 0.844 | – | 41.3 | – | 14.3 | 44.3 |
HDA | 4 | 0.262 | 0.642 | 0.557 | 0.497 | 28.630 | 0.268 | – | – | 31.2 | 37.9 | 30.9 |
SEHD | 9 | 0.525 | 0.529 | 0.891 | 0.253 | 78.468 | 0.807 | 9.6 | 43.7 | 24.5 | 22.2 | – |
SEHA | 6 | 0.287 | 0.642 | 0.788 | 0.348 | 55.196 | 0.483 | 9.0 | 42.7 | 23.5 | – | 24.8 |
SEDA | 9 | 0.324 | 0.632 | 0.854 | 0.293 | 55.962 | 0.600 | 10.4 | 44.7 | – | 20.5 | 24.4 |
SHDA | 4 | 0.238 | 0.652 | 0.554 | 0.499 | 28.202 | 0.241 | 9.7 | – | 25.8 | 37.3 | 27.3 |
EHDA | 9 | 0.433 | 0.579 | 0.893 | 0.251 | 79.732 | 0.709 | – | 36.5 | 21.3 | 19.8 | 22.4 |
SEHDA | 9 | 0.445 | 0.572 | 0.898 | 0.246 | 83.748 | 0.720 | 6.7 | 34.8 | 18.6 | 19.3 | 20.6 |
2.2. Graphical Interpretation of CoMSIA Model
2.3. Molecule Docking
2.3.1. Docking Validation
2.3.2. Ligand-Binding Pocket
2.4. Comparing the Results of 3D Contour Maps with Docking
2.5. MD Simulations
3. Methodology
3.1. Data Source for Computational Modeling
No. | Structure | Ki (μM) | No. | Structure | Ki (μM) |
---|---|---|---|---|---|
001 | | 0.0004 | 068 | | 0.162 |
009 $ | | 0.008 | 072 $ | | 0.0049 |
015 | | 0.004 | 080 | | 0.0044 |
027 $ | | 0.063 | 085 | | 0.0039 |
037 | | 0.089 | 093 | | 0.0029 |
046 | | 0.0027 | 102 $ | | 0.009 |
052 | | 0.0072 | 107 | | 0.12 |
063 | | 0.249 | 123 | | 0.063 |
3.2. Geometry Optimization and Alignment
3.3. Building Atom-Based 3D-QSAR Models
3.4. Analysis of Molecular Docking
3.5. Docking Reliability Validated by the Re-Dock Procedure
3.6. MD Simulations of Complexes
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Yang, Y.; Li, Y.; Pan, Y.; Wang, J.; Lin, F.; Wang, C.; Zhang, S.; Yang, L. Computational Analysis of Structure-Based Interactions for Novel H1-Antihistamines. Int. J. Mol. Sci. 2016, 17, 129. https://doi.org/10.3390/ijms17010129
Yang Y, Li Y, Pan Y, Wang J, Lin F, Wang C, Zhang S, Yang L. Computational Analysis of Structure-Based Interactions for Novel H1-Antihistamines. International Journal of Molecular Sciences. 2016; 17(1):129. https://doi.org/10.3390/ijms17010129
Chicago/Turabian StyleYang, Yinfeng, Yan Li, Yanqiu Pan, Jinghui Wang, Feng Lin, Chao Wang, Shuwei Zhang, and Ling Yang. 2016. "Computational Analysis of Structure-Based Interactions for Novel H1-Antihistamines" International Journal of Molecular Sciences 17, no. 1: 129. https://doi.org/10.3390/ijms17010129