Construction of Quantitative Structure Activity Relationship (QSAR) Models to Predict Potency of Structurally Diversed Janus Kinase 2 Inhibitors
Abstract
:1. Introduction
2. Results
2.1. Chemical Space of JAK2 Inhibitors
2.2. QSAR Modeling
2.3. Interpretation of QSAR Models
2.4. Applicability Domain
2.5. Molecular Cluster Analysis of JAK2 Inhibitors
3. Materials and Methods
3.1. Data Set
3.1.1. Description of Compounds
3.1.2. Feature Selection
3.1.3. Data Splitting
3.1.4. Multivariate Analysis
3.2. Validation of QSAR Models
3.3. Applicability Domain Analysis
3.4. Molecular Cluster Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
JAK2 | Janus Kinase 2 |
QSAR | Quantitative Structure-Activity Relationship |
DT | Decision Tree |
SVM | Support Vector Machine |
DNN | Deep Neural Network |
RF | Random Forest |
RMSE | Root Mean Square Error |
CV | Cross Validation |
OECD | Organisation for Economic Cooperation and Development |
MW | Molecular Weight |
ALogP | Octanol-Water Partition Coefficient |
nHBDon | Number of Hydrogen Bond Donors |
nHBAcc | Number of Hydrogen Bond Acceptors |
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Sample Availability: Samples of the compounds are not available from the authors. |
Models | Training Set | 10-Fold CV | Test Set | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
RMSE | RMSE | RMSE | ||||||||||||
DT | 0.65 ± 0.02 | 0.72 ± 0.02 | 0.65 ± 0.02 | 0.28 ± 0.01 | 0.45 ± 0.07 | 0.91 ± 0.06 | 0.40 ± 0.09 | 0.20 ± 0.06 | 0.29 ± 0.05 | 1.02 ± 0.04 | 0.28 ± 0.05 | 0.31 ± 0.05 | ||
SVM | 0.72 ± 0.01 | 0.65 ± 0.02 | 0.66 ± 0.02 | 0.26 ± 0.01 | 0.57 ± 0.05 | 0.80 ± 0.06 | 0.54 ± 0.04 | 0.33 ± 0.03 | 0.58 ± 0.05 | 0.79 ± 0.05 | 0.56 ± 0.03 | 0.33 ± 0.02 | ||
DNN | 0.59 ± 0.04 | 0.82 ± 0.07 | 0.57 ± 0.04 | 0.32 ± 0.03 | 0.47 ± 0.07 | 0.93 ± 0.08 | 0.43 ± 0.07 | 0.29 ± 0.08 | 0.49 ± 0.04 | 0.90 ± 0.06 | 0.47 ± 0.04 | 0.31 ± 0.05 | ||
RF | 0.75 ± 0.02 | 0.62 ± 0.02 | 0.69 ± 0.01 | 0.24 ± 0.01 | 0.74 ± 0.05 | 0.63 ± 0.05 | 0.67 ± 0.04 | 0.25 ± 0.03 | 0.75 ± 0.03 | 0.62 ± 0.04 | 0.68 ± 0.03 | 0.25 ± 0.02 |
Models | Training Set | 10-Fold CV | Test Set | |||
---|---|---|---|---|---|---|
MAE | MAE | MAE | ||||
DT | 0.53 ± 0.02 | 0.65 ± 0.05 | 0.76 ± 0.03 | |||
SVM | 0.42 ± 0.02 | 0.55 ± 0.04 | 0.54 ± 0.03 | |||
DNN | 0.64 ± 0.06 | 0.71 ± 0.07 | 0.70 ± 0.05 | |||
RF | 0.42 ± 0.01 | 0.43 ± 0.04 | 0.42 ± 0.02 |
Fingerprints | Description |
---|---|
SubFPC1 | Primary Carbon |
SubFPC2 | Secondary Carbon |
SubFPC3 | Tertiary Carbon |
SubFPC4 | Quaternary Carbon |
SubFPC5 | Alkene |
SubFPC12 | Alcohol |
SubFPC16 | Dialkylether |
SubFPC18 | Alkylarylether |
SubFPC26 | Tertiary Aliphalitic Amine |
SubFPC28 | Primary Aromatic Amine |
SubFPC32 | Secondary Mixed Amine |
SubFPC33 | Tertiary Mixed Amine |
SubFPC88 | Carboxylic Acid derivative |
SubFPC99 | Primary Amide |
SubFPC100 | Secondary Amide |
SubFPC101 | Tertiary Amide |
SubFPC133 | Nitrile |
SubFPC137 | Vinylogous Ester |
SubFPC143 | Carbonic Acid Derivatives |
SubFPC171 | Arylchloride |
SubFPC172 | Arylfluoride |
SubFPC179 | Hetero N basic H |
SubFPC180 | Hetero N basic no H |
SubFPC184 | Heteroaromatic |
SubFPC200 | Sulfon |
SubFPC214 | Sulfonic Derivative |
SubFPC279 | Annelated Rings |
SubFPC287 | Spiro |
SubFPC294 | Trifluoromethyl |
SubFPC295 | C ONS Bond |
SubFPC301 | 1,5-Tautomerizable |
SubFPC302 | Rotatable Bond |
SubFPC307 | Chiral Center Specified |
Cluster No. | pIC | N | MW | AlogP |
---|---|---|---|---|
1 | 7.30 ± 1.12 | 876 | 456.11 ± 75.65 | 3.87 ± 1.16 |
2 | 7.57 ± 0.68 | 491 | 432.38 ± 58.91 | 3.59 ± 0.95 |
3 | 7.70 ± 0.81 | 137 | 455.01 ± 43.35 | 1.68 ± 0.99 |
4 | 6.98 ± 0.52 | 23 | 333.59 ± 55.50 | 2.01 ± 1.01 |
5 | 9.76 ± 0.75 | 58 | 385.45 ± 33.55 | 1.11 ± 0.69 |
6 | 10.04 ± 0.32 | 38 | 461.42 ± 44.55 | 0.74 ± 0.98 |
7 | 6.48 ± 0.41 | 25 | 436.48 ± 34.56 | 2.33 ± 0.95 |
8 | 8.12 ± 1.09 | 25 | 441.67 ± 24.85 | 3.78 ± 0.50 |
9 | 6.06 ± 0.85 | 20 | 287.99 ± 30.95 | 1.30 ± 1.59 |
10 | 6.97 ± 0.44 | 24 | 283.09 ± 15.28 | 1.68 ± 0.48 |
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Simeon, S.; Jongkon, N. Construction of Quantitative Structure Activity Relationship (QSAR) Models to Predict Potency of Structurally Diversed Janus Kinase 2 Inhibitors. Molecules 2019, 24, 4393. https://doi.org/10.3390/molecules24234393
Simeon S, Jongkon N. Construction of Quantitative Structure Activity Relationship (QSAR) Models to Predict Potency of Structurally Diversed Janus Kinase 2 Inhibitors. Molecules. 2019; 24(23):4393. https://doi.org/10.3390/molecules24234393
Chicago/Turabian StyleSimeon, Saw, and Nathjanan Jongkon. 2019. "Construction of Quantitative Structure Activity Relationship (QSAR) Models to Predict Potency of Structurally Diversed Janus Kinase 2 Inhibitors" Molecules 24, no. 23: 4393. https://doi.org/10.3390/molecules24234393