Background
Methods
Data
Transcriptional drug repositioning approach
Machine learning approach
Target prediction
Pathway annotation
Synergy model generation
Computational validation for drug combination
Prospective utilisation of the synergy model
Experimental validation of compounds for malaria
Results
Prospective validation of single agents
Compound | Class 3D7 | Class DD2 | Class HB3 | AC50 3D7 | AC50 DD2 | AC50 HB3 | Average AC50 |
---|---|---|---|---|---|---|---|
CHR | − 1.1 | − 1.1 | − 1.1 |
0.0119
|
0.0106
|
0.0106
|
0.011
|
FUL | − 1.1 | − 1.1 | − 1.1 |
0.0335
|
0.0335
|
0.1332
|
0.0667
|
API | − 1.1 | − 1.1 | − 1.1 |
0.0749
|
0.0841
|
0.0749
|
0.078
|
ING | − 1.1 | − 1.1 | − 1.1 | 1.3324 | 1.495 | 1.495 | 1.4408 |
MON | − 2.1 | − 2.1 | − 2.3 | 1.4956 | 1.0588 | 1.8828 | 1.4791 |
RAL | − 1.1 | − 1.1 | − 2.1 |
0.7493
|
0.3347
| 4.7277 | 1.9372 |
TAC | − 1.1 | − 1.1 | − 1.1 | 1.8821 | 3.7553 | 1.6774 | 2.4383 |
CHE | 1.3 | − 2.3 | 1.3 |
0.0266
| 10.5839 |
0.0011
| 3.5372 |
JX4 | − 1.1 | − 1.1 | − 2.1 | 0.7493 |
0.0595
| 10.5839 | 3.7976 |
HYD | − 1.1 | − 1.1 | − 2.1 | 2.6586 | 1.6774 | 11.8754 | 5.4038 |
THI | − 2.1 | − 2.1 | − 2.1 | 10.5839 | 14.9502 | 14.9502 | 13.4948 |
MEG | − 2.1 | − 1.1 | − 2.1 | 14.9502 | 1.8821 | 23.6945 | 13.5089 |
PI8 | − 2.3 | − 2.1 | − 2.1 | 13.3244 | 11.8754 | 16.7744 | 13.9914 |
KIN | − 2.1 | − 2.1 | − 2.1 | 13.3244 | 21.1177 | 16.7744 | 17.0722 |
Prospective validation of drug combinations
Compund 1 | Compound 2 | 3D7 Pred | 3D7 Gamma | DD2 Pred | DD2 Gamma | HB3 Pred | HB3 Gamma |
---|---|---|---|---|---|---|---|
TAC | HYD | 0.309 | 0.948** | 0.189 | 0.885** |
0.501
| 0.951* |
FUL | TAC | 0.627 | 0.961* |
0.612
| 0.908** |
0.659
|
0.989
|
ING | TAC |
0.820
| 0.954* |
0.674
| 0.917** |
0.854
| 0.954* |
FUL | MEG |
0.722
| 1.007 |
0.583
| 0.918** |
0.745
| 0.970* |
MEG | HYD |
0.784
|
0.985
|
0.629
| 0.920** |
0.738
|
0.988
|
KIN | HYD | 0.475 |
0.984
| 0.371 | 0.938** | 0.477 |
0.977
|
API | TAC | 0.416 | 0.975* |
0.685
| 0.942** |
0.523
| 0.946** |
FUL | RAL |
0.792
|
0.980
|
0.739
| 0.952* |
0.825
| 0.966* |
API | HYD |
0.806
|
0.987
|
0.717
| 0.952* |
0.501
| 0.968* |
FUL | THI |
0.651
|
0.982
|
0.714
| 0.954* |
0.540
| 0.960* |
THI | RAL |
0.549
| 0.931** |
0.698
| 0.956* | 0.375 | 0.911** |
PI8 | HYD | 0.278 |
0.977
| 0.293 | 0.961* | 0.171 |
0.993
|
FUL | HYD |
0.788
| 0.965* |
0.747
| 0.962* |
0.734
| 0.951* |
TAC | RAL | 0.483 |
0.995
| 0.342 | 0.964* |
0.612
| 0.962* |
ING | JX4 |
0.859
|
0.980
|
0.740
| 0.968* |
0.826
| 0.975* |
MEG | RAL |
0.795
| 0.937** |
0.648
| 0.969* |
0.791
| 0.966* |
ING | RAL |
0.836
| 0.964* |
0.658
| 0.975* |
0.793
| 0.966* |
API | RAL |
0.814
| 0.997 |
0.697
|
0.976
| 0.472 |
0.992
|
CHR | HYD |
0.633
| 1.001 | 0.238 |
0.979
|
0.644
|
0.991
|
KIN | JX4 |
0.510
|
0.987
|
0.530
|
0.982
| 0.479 |
0.989
|
API | JX4 |
0.761
| 1.020 |
0.723
|
0.984
| 0.495 | 0.970* |
CHR | TAC | 0.418 |
0.99
| 0.163 |
0.987
| 0.445 | 0.996 |
JX4 | HYD | 0.498 |
0.984
|
0.503
|
0.987
| 0.498 |
0.986
|
PI8 | ING |
0.551
| 0.975* | 0.443 |
0.991
| 0.499 |
0.989
|
PI8 | JX4 | 0.238 |
0.990
|
0.621
|
0.994
| 0.214 |
0.981
|
PI8 | RAL | 0.369 | 1.014 | 0.293 | 0.997 | 0.126 |
0.995
|
CHR | JX4 |
0.709
|
0.990
| 0.355 | 0.999 |
0.608
|
0.991
|
API | MEG |
0.776
|
0.981
|
0.632
| 1.004 |
0.582
|
0.979
|
CHR | MEG |
0.817
|
0.995
|
0.568
| 1.010 |
0.791
|
0.985
|
PI8 | TAC | 0.283 |
0.986
| 0.205 | 1.014 | 0.118 |
0.983
|
API | CHR |
0.785
| 0.999 |
0.722
| 1.014 |
0.525
| 0.998 |
CHR | RAL |
0.785
|
0.990
| 0.442 | 1.019 |
0.695
| 1.004 |
PI8 | MEG | 0.491 | 0.972* | 0.366 | 1.021 | 0.272 | 0.966* |
ING | HYD |
0.869
|
0.985
|
0.699
| 1.021 |
0.810
|
0.992
|
PI8 | KIN | 0.246 |
0.989
| 0.348 | 1.046 | 0.197 | 0.997 |
Compound 1 | Compound 2 | 3D7 Gamma | DD2 Gamma | HB3 Gamma |
---|---|---|---|---|
Mefloquine | Artesunate | 0.911** | 0.786** | 0.797** |
Amodiaquine | Artesunate |
0.993
| 1.064 | 0.955* |
Sulfadoxine | Artesunate | 0.986 | 1.016 | 0.936** |
Lumefantrine | Artemether | 2.221 | 1.058 | 0.997 |
Piperaquine | Dihydroartemisinin (DHA) | 0.999 | 1.007 | 0.999 |
Strain | Mild-to-strong synergy (gamma ≤ 0.995) | Moderate-to-strong synergy (gamma ≤ 0.975) | Strong synergy (gamma ≤ 0.95) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
3D7 | DD2 | HB3 | AVG | 3D7 | DD2 | HB3 | AVG | 3D7 | DD2 | HB3 | AVG | |
True positives | 18 | 18 | 19 | 18.3 | 7 | 13 | 12 | 10.7 | 2 | 5 | 1 | 2.7 |
False negatives | 11 | 7 | 12 | 10.0 | 3 | 4 | 3 | 3.3 | 1 | 2 | 1 | 1.3 |
False positives | 5 | 4 | 2 | 3.7 | 16 | 9 | 9 | 11.3 | 21 | 17 | 20 | 19.3 |
Precision (%) | 78.3 | 81.8 | 90.5 | 83.3 | 30.4 | 59.1 | 57.1 | 48.5 | 8.7 | 22.7 | 4.8 | 12.1 |
Recall (%) | 62.1 | 72.0 | 61.3 | 64.7 | 70.0 | 76.5 | 80.0 | 76.2 | 66.7 | 71.4 | 50.0 | 66.7 |
F measure (%) | 69.2 | 76.6 | 73.1 | 72.8 | 42.4 | 66.7 | 66.7 | 59.3 | 15.4 | 34.5 | 8.7 | 20.5 |
Training set synergies (%) | 42.8 | 41.2 | 40.0 | 41.3 | 25.7 | 25.3 | 23.0 | 24.7 | 15.8 | 15.6 | 13.4 | 14.9 |
Discussion
Mechanistic justification of the compounds
Limitations of the study
Performance evaluation and effect of gamma choice
Conclusions
Compound | Maximum plasma concentration, CMax (ng/mL) | Molar mass (g/mol) | Maximal dose (nM) | Refs |
---|---|---|---|---|
FUL | 12.6 | 606.772 | 20.8 | [53] |
RAL | 1 | 473.584 | 2.1 | [54] |
THI | 205.5 | 370.577 | 554 | [55] |
MEG | 412 | 384.516 | 1071 | [56] |
TAC | 15.8 | 804.018 | 19.6 | [57] |
HYD | 32 | 374.904 | 85.3 | [58] |
API | 341.6 ± 85.2 | 623.79 | 547.6 ± 136.6 | [59] |
CHR | 1.85 | 1183.25 | 1.5 | [60] |