Three-Dimensional Biologically Relevant Spectrum (BRS-3D): Shape Similarity Profile Based on PDB Ligands as Molecular Descriptors
Abstract
:1. Introduction
2. Results
2.1. Summary of BRCD-3D
2.2. Evaluation with GLL/GDD (G Protein-Coupled Receptor (GPCR) Ligand Library and the GPCR Decoy Database) Benchmark Data Sets
2.3. Feature Selection
2.4. Comparison with Other Molecular Descriptors
2.5. HDAC1 Inhibitor Screening
2.6. Application of BRS-3D in Subtype Selectivity Predictions
3. Discussion
4. Materials and Methods
4.1. Workflow of BRS-3D-Based Virtual Screening
4.2. Surflex-Sim Superimposition
4.3. Construction of the BRCD-3D
4.4. Calculation of BRS-3D
4.5. The Benchmark Data Sets
4.6. Model Development and Validation
4.7. Feature Selection
4.8. Dragon 2D Descriptors and MOE 3D Descriptors
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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No. | Data Sets | CV AUC | Accuray | Precision | Recall | MCC |
---|---|---|---|---|---|---|
1 | 5HT1A_Agonist | 0.989 | 0.994 | 0.986 | 0.763 | 0.865 |
2 | 5HT1A_Antagonist | 0.975 | 0.992 | 0.888 | 0.782 | 0.829 |
3 | 5HT1D_Agonist | 0.988 | 0.993 | 1.000 | 0.703 | 0.835 |
4 | 5HT1D_Antagonist | 0.980 | 0.995 | 0.981 | 0.825 | 0.898 |
5 | 5HT2A_Antagonist | 0.981 | 0.992 | 0.894 | 0.759 | 0.820 |
6 | 5HT2C_Agonist | 0.983 | 0.986 | 0.721 | 0.738 | 0.722 |
7 | 5HT2C_Antagonist | 0.957 | 0.991 | 1.000 | 0.625 | 0.787 |
8 | 5HT4R_Agonist | 0.992 | 0.991 | 1.000 | 0.638 | 0.795 |
9 | 5HT4R_Antagonist | 0.993 | 0.997 | 1.000 | 0.875 | 0.933 |
10 | AA1R_Antagonist | 0.986 | 0.992 | 0.894 | 0.750 | 0.814 |
11 | AA2AR_Antagonist | 0.985 | 0.995 | 0.983 | 0.808 | 0.889 |
12 | AA2BR_Antagonist | 0.984 | 0.993 | 0.894 | 0.797 | 0.841 |
13 | ACM1_Agonist | 0.985 | 0.992 | 0.851 | 0.820 | 0.831 |
14 | ACM3_Antagonist | 0.983 | 0.991 | 0.930 | 0.678 | 0.790 |
15 | ADA1A_Antagonist | 0.983 | 0.993 | 0.968 | 0.763 | 0.856 |
16 | ADA1B_Antagonist | 0.988 | 0.994 | 0.889 | 0.873 | 0.878 |
17 | ADA1D_Antagonist | 0.987 | 0.994 | 0.948 | 0.807 | 0.872 |
18 | ADA2A_Antagonist | 0.953 | 0.991 | 0.983 | 0.648 | 0.794 |
19 | ADA2B_Antagonist | 0.959 | 0.979 | 0.562 | 0.839 | 0.677 |
20 | ADA2C_Antagonist | 0.961 | 0.992 | 0.967 | 0.686 | 0.811 |
21 | ADRB1_Agonist | 0.995 | 0.992 | 0.912 | 0.738 | 0.816 |
22 | ADRB1_Antagonist | 0.986 | 0.991 | 0.964 | 0.643 | 0.783 |
23 | ADRB2_Agonist | 0.992 | 0.996 | 0.904 | 0.927 | 0.914 |
24 | ADRB2_Antagonist | 0.990 | 0.995 | 0.971 | 0.829 | 0.895 |
25 | ADRB3_Agonist | 0.994 | 0.996 | 0.982 | 0.860 | 0.917 |
26 | AG2R_Antagonist | 0.996 | 0.998 | 0.996 | 0.907 | 0.949 |
27 | CCKAR_Antagonist | 0.986 | 0.993 | 1.000 | 0.722 | 0.847 |
28 | CLTR1_Antagonist | 0.981 | 0.992 | 0.979 | 0.701 | 0.825 |
29 | DRD2_Antagonist | 0.977 | 0.992 | 0.951 | 0.726 | 0.827 |
30 | DRD3_Antagonist | 0.982 | 0.993 | 0.941 | 0.750 | 0.837 |
31 | DRD4_Antagonist | 0.993 | 0.995 | 0.982 | 0.827 | 0.899 |
32 | EDNRA_Antagonist | 0.987 | 0.994 | 0.932 | 0.809 | 0.865 |
33 | EDNRB_Antagonist | 0.986 | 0.993 | 0.902 | 0.814 | 0.853 |
34 | GASR_Antagonist | 0.990 | 0.995 | 0.979 | 0.816 | 0.891 |
35 | HRH3_Antagonist | 0.997 | 0.992 | 0.958 | 0.730 | 0.833 |
36 | LSHR_Antagonist | 0.990 | 0.989 | 1.000 | 0.543 | 0.733 |
37 | NK1R_Antagonist | 0.980 | 0.991 | 0.914 | 0.711 | 0.802 |
38 | OPRD_Agonist | 0.990 | 0.993 | 1.000 | 0.722 | 0.847 |
39 | OPRK_Agonist | 0.990 | 0.990 | 1.000 | 0.596 | 0.768 |
40 | TA2R_Antagonist | 0.991 | 0.994 | 0.974 | 0.772 | 0.864 |
41 | V1AR_Antagonist | 0.986 | 0.993 | 0.971 | 0.733 | 0.840 |
42 | V1BR_Antagonist | 0.983 | 0.992 | 0.969 | 0.689 | 0.813 |
Data Sets | Accuracy | Precision | Recall | MCC | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Dragon 2D | MOE 3D | BRS-3D | Dragon 2D | MOE 3D | BRS-3D | Dragon 2D | MOE 3D | BRS-3D | Dragon 2D | MOE 3D | BRS-3D | |
1 | 0.993 | 0.951 | 0.994 | 0.849 | 0.330 | 0.986 | 0.889 | 0.932 | 0.763 | 0.866 | 0.539 | 0.865 |
2 | 0.992 | 0.991 | 0.992 | 0.819 | 0.814 | 0.888 | 0.851 | 0.822 | 0.782 | 0.831 | 0.813 | 0.829 |
3 | 0.987 | 0.977 | 0.993 | 0.671 | 0.526 | 1.000 | 0.919 | 0.919 | 0.703 | 0.779 | 0.686 | 0.835 |
4 | 0.981 | 0.992 | 0.995 | 0.568 | 0.831 | 0.981 | 0.921 | 0.857 | 0.825 | 0.715 | 0.840 | 0.898 |
5 | 0.964 | 0.945 | 0.992 | 0.401 | 0.300 | 0.894 | 0.883 | 0.903 | 0.759 | 0.581 | 0.502 | 0.820 |
6 | 0.987 | 0.980 | 0.986 | 0.744 | 0.571 | 0.721 | 0.762 | 0.857 | 0.738 | 0.747 | 0.691 | 0.722 |
7 | 0.983 | 0.949 | 0.991 | 0.636 | 0.317 | 1.000 | 0.766 | 0.906 | 0.625 | 0.690 | 0.519 | 0.787 |
8 | 0.998 | 0.979 | 0.991 | 0.939 | 0.541 | 1.000 | 0.979 | 0.979 | 0.638 | 0.957 | 0.719 | 0.795 |
9 | 0.995 | 0.994 | 0.997 | 0.855 | 0.863 | 1.000 | 0.979 | 0.917 | 0.875 | 0.912 | 0.886 | 0.933 |
10 | 0.990 | 0.986 | 0.992 | 0.774 | 0.705 | 0.894 | 0.857 | 0.769 | 0.750 | 0.810 | 0.729 | 0.814 |
11 | 0.989 | 0.982 | 0.995 | 0.756 | 0.602 | 0.983 | 0.808 | 0.808 | 0.808 | 0.776 | 0.689 | 0.889 |
12 | 0.987 | 0.978 | 0.993 | 0.794 | 0.539 | 0.894 | 0.676 | 0.865 | 0.797 | 0.726 | 0.672 | 0.841 |
13 | 0.986 | 0.962 | 0.992 | 0.662 | 0.383 | 0.851 | 0.888 | 0.882 | 0.820 | 0.760 | 0.567 | 0.831 |
14 | 0.988 | 0.982 | 0.991 | 0.714 | 0.605 | 0.930 | 0.847 | 0.831 | 0.678 | 0.772 | 0.700 | 0.790 |
15 | 0.980 | 0.960 | 0.993 | 0.557 | 0.373 | 0.968 | 0.915 | 0.881 | 0.763 | 0.705 | 0.558 | 0.856 |
16 | 0.990 | 0.955 | 0.994 | 0.758 | 0.349 | 0.889 | 0.882 | 0.927 | 0.873 | 0.812 | 0.554 | 0.878 |
17 | 0.977 | 0.955 | 0.994 | 0.528 | 0.347 | 0.948 | 0.904 | 0.904 | 0.807 | 0.681 | 0.544 | 0.872 |
18 | 0.957 | 0.938 | 0.991 | 0.359 | 0.270 | 0.983 | 0.909 | 0.864 | 0.648 | 0.556 | 0.462 | 0.794 |
19 | 0.973 | 0.982 | 0.979 | 0.471 | 0.632 | 0.562 | 0.736 | 0.690 | 0.839 | 0.576 | 0.651 | 0.677 |
20 | 0.955 | 0.978 | 0.992 | 0.335 | 0.542 | 0.967 | 0.837 | 0.674 | 0.686 | 0.513 | 0.593 | 0.811 |
21 | 0.986 | 0.974 | 0.992 | 0.655 | 0.494 | 0.912 | 0.905 | 0.905 | 0.738 | 0.763 | 0.658 | 0.816 |
22 | 0.989 | 0.977 | 0.991 | 0.702 | 0.522 | 0.964 | 0.952 | 0.857 | 0.643 | 0.812 | 0.659 | 0.783 |
23 | 0.995 | 0.987 | 0.996 | 0.900 | 0.694 | 0.904 | 0.878 | 0.829 | 0.927 | 0.886 | 0.752 | 0.914 |
24 | 0.974 | 0.971 | 0.995 | 0.452 | 0.429 | 0.971 | 0.917 | 0.917 | 0.829 | 0.633 | 0.616 | 0.895 |
25 | 0.990 | 0.986 | 0.996 | 0.738 | 0.665 | 0.982 | 0.938 | 0.907 | 0.860 | 0.827 | 0.770 | 0.917 |
26 | 0.996 | 0.994 | 0.998 | 0.877 | 0.843 | 0.996 | 0.967 | 0.927 | 0.907 | 0.918 | 0.881 | 0.949 |
27 | 0.992 | 0.972 | 0.993 | 0.857 | 0.467 | 1.000 | 0.833 | 0.875 | 0.722 | 0.841 | 0.627 | 0.847 |
28 | 0.994 | 0.968 | 0.992 | 0.857 | 0.441 | 0.979 | 0.896 | 0.940 | 0.701 | 0.873 | 0.632 | 0.825 |
29 | 0.964 | 0.987 | 0.992 | 0.403 | 0.699 | 0.951 | 0.925 | 0.811 | 0.726 | 0.597 | 0.746 | 0.827 |
30 | 0.948 | 0.975 | 0.993 | 0.313 | 0.500 | 0.941 | 0.891 | 0.734 | 0.750 | 0.510 | 0.594 | 0.837 |
31 | 0.981 | 0.975 | 0.995 | 0.575 | 0.502 | 0.982 | 0.955 | 0.955 | 0.827 | 0.733 | 0.683 | 0.899 |
32 | 0.994 | 0.951 | 0.994 | 0.864 | 0.329 | 0.932 | 0.890 | 0.912 | 0.809 | 0.874 | 0.531 | 0.865 |
33 | 0.990 | 0.975 | 0.993 | 0.758 | 0.505 | 0.902 | 0.858 | 0.912 | 0.814 | 0.801 | 0.668 | 0.853 |
34 | 0.994 | 0.981 | 0.995 | 0.861 | 0.582 | 0.979 | 0.921 | 0.904 | 0.816 | 0.887 | 0.717 | 0.891 |
35 | 0.977 | 0.988 | 0.992 | 0.524 | 0.736 | 0.958 | 0.857 | 0.841 | 0.730 | 0.660 | 0.781 | 0.833 |
36 | 0.986 | 0.985 | 0.989 | 0.733 | 0.744 | 1.000 | 0.717 | 0.630 | 0.543 | 0.718 | 0.677 | 0.733 |
37 | 0.992 | 0.992 | 0.991 | 0.805 | 0.830 | 0.914 | 0.872 | 0.839 | 0.711 | 0.834 | 0.830 | 0.802 |
38 | 0.994 | 0.946 | 0.993 | 0.867 | 0.307 | 1.000 | 0.903 | 0.917 | 0.722 | 0.882 | 0.513 | 0.847 |
39 | 0.995 | 0.935 | 0.990 | 0.869 | 0.251 | 1.000 | 0.930 | 0.807 | 0.596 | 0.896 | 0.428 | 0.768 |
40 | 0.973 | 0.988 | 0.994 | 0.479 | 0.721 | 0.974 | 0.945 | 0.876 | 0.772 | 0.662 | 0.789 | 0.864 |
41 | 0.994 | 0.987 | 0.993 | 0.870 | 0.800 | 0.971 | 0.889 | 0.622 | 0.733 | 0.876 | 0.699 | 0.840 |
42 | 0.992 | 0.969 | 0.992 | 0.768 | 0.435 | 0.969 | 0.956 | 0.822 | 0.689 | 0.853 | 0.585 | 0.813 |
No. | Target | Target Name | Ligand Type | Ligand Count | Decoy Count |
---|---|---|---|---|---|
1 | 5HT1A | 5-hydroxytryptamine receptor 1A | Agonist | 952 | 37,128 |
2 | 5HT1A | 5-hydroxytryptamine receptor 1A | Antagonist | 506 | 19,734 |
3 | 5HT1D | 5-hydroxytryptamine receptor 1D | Agonist | 558 | 21,762 |
4 | 5HT1D | 5-hydroxytryptamine receptor 1D | Antagonist | 315 | 12,285 |
5 | 5HT2A | 5-hydroxytryptamine receptor 2A | Antagonist | 725 | 28,275 |
6 | 5HT2C | 5-hydroxytryptamine receptor 2C | Agonist | 209 | 8151 |
7 | 5HT2C | 5-hydroxytryptamine receptor 2C | Antagonist | 318 | 12,402 |
8 | 5HT4R | 5-hydroxytryptamine receptor 4 | Agonist | 235 | 9165 |
9 | 5HT4R | 5-hydroxytryptamine receptor 4 | Antagonist | 241 | 9399 |
10 | AA1R | Adenosine receptor A1 | Antagonist | 280 | 10,920 |
11 | AA2AR | Adenosine receptor A2a | Antagonist | 361 | 14,079 |
12 | AA2BR | Adenosine receptor A2b | Antagonist | 370 | 14,430 |
13 | ACM1 | Muscarinic acetylcholine receptor M1 | Agonist | 806 | 31,434 |
14 | ACM3 | Muscarinic acetylcholine receptor M3 | Antagonist | 295 | 11,505 |
15 | ADA1A | Alpha-1A adrenergic receptor | Antagonist | 588 | 22,932 |
16 | ADA1B | Alpha-1B adrenergic receptor | Antagonist | 550 | 21,450 |
17 | ADA1D | Alpha-1D adrenergic receptor | Antagonist | 568 | 22,152 |
18 | ADA2A | Alpha-2A adrenergic receptor | Antagonist | 440 | 17,160 |
19 | ADA2B | Alpha-2B adrenergic receptor | Antagonist | 437 | 17,043 |
20 | ADA2C | Alpha-2C adrenergic receptor | Antagonist | 433 | 16,887 |
21 | ADRB1 | Beta-1 adrenergic receptor | Agonist | 209 | 8151 |
22 | ADRB1 | Beta-1 adrenergic receptor | Antagonist | 211 | 8229 |
23 | ADRB2 | Beta-2 adrenergic receptor | Agonist | 206 | 8034 |
24 | ADRB2 | Beta-2 adrenergic receptor | Antagonist | 204 | 7956 |
25 | ADRB3 | Beta-3 adrenergic receptor | Agonist | 643 | 25,077 |
26 | AG2R | Type-1 angiotensin II receptor | Antagonist | 1502 | 58,578 |
27 | CCKAR | Cholecystokinin receptor type A | Antagonist | 360 | 14,040 |
28 | CLTR1 | Cysteinyl leukotriene receptor 1 | Antagonist | 333 | 12,987 |
29 | DRD2 | D2 dopamine receptor | Antagonist | 529 | 20,631 |
30 | DRD3 | D3 dopamine receptor | Antagonist | 317 | 12,363 |
31 | DRD4 | D4 dopamine receptor | Antagonist | 665 | 25,935 |
32 | EDNRA | Endothelin-1 receptor | Antagonist | 676 | 26,364 |
33 | EDNRB | Endothelin B receptor | Antagonist | 561 | 21,879 |
34 | GASR | Gastrin/cholecystokinin type B receptor | Antagonist | 567 | 22,113 |
35 | HRH3 | Histamine H3 receptor | Antagonist | 313 | 12,207 |
36 | LSHR | Lutropin-choriogonadotropic hormone receptor | Antagonist | 230 | 8970 |
37 | NK1R | Substance-P receptor | Antagonist | 900 | 35,100 |
38 | OPRD | Delta-type opioid receptor | Agonist | 361 | 14,079 |
39 | OPRK | Kappa-type opioid receptor | Agonist | 284 | 11,076 |
40 | TA2R | Thromboxane A2 receptor | Antagonist | 725 | 28,275 |
41 | V1AR | Vasopressin V1a receptor | Antagonist | 225 | 8775 |
42 | V1BR | Vasopressin V1b receptor | Antagonist | 225 | 8775 |
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Hu, B.; Kuang, Z.-K.; Feng, S.-Y.; Wang, D.; He, S.-B.; Kong, D.-X. Three-Dimensional Biologically Relevant Spectrum (BRS-3D): Shape Similarity Profile Based on PDB Ligands as Molecular Descriptors. Molecules 2016, 21, 1554. https://doi.org/10.3390/molecules21111554
Hu B, Kuang Z-K, Feng S-Y, Wang D, He S-B, Kong D-X. Three-Dimensional Biologically Relevant Spectrum (BRS-3D): Shape Similarity Profile Based on PDB Ligands as Molecular Descriptors. Molecules. 2016; 21(11):1554. https://doi.org/10.3390/molecules21111554
Chicago/Turabian StyleHu, Ben, Zheng-Kun Kuang, Shi-Yu Feng, Dong Wang, Song-Bing He, and De-Xin Kong. 2016. "Three-Dimensional Biologically Relevant Spectrum (BRS-3D): Shape Similarity Profile Based on PDB Ligands as Molecular Descriptors" Molecules 21, no. 11: 1554. https://doi.org/10.3390/molecules21111554