Theoretical Studies Aimed at Finding FLT3 Inhibitors and a Promising Compound and Molecular Pattern with Dual Aurora B/FLT3 Activity
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Data Set
4.2. Predicted Model
- i)
- Coefficient of determination (R2): is the proportion of the variance in the dependent variable that is predictable from the independent variable.
- ii)
- Leave-one-out cross-validation (LOOcv) correlation coefficient (q2): estimating the performance of a predictive model.
- iii)
- Y-Randomization (R2rand): consists of the random exchange of the independent variable values. Thus, the R2rand value must be less than the correlation coefficient of the non-randomized models.
- iv)
- R2p: penalizes the model for the difference between R2 of randomized models and the R2 of the non-randomized model:
- v)
- Correlation coefficient of external validation set (R2pred): reflects the degree of correlation between the observed (YExp(test)) and predicted (YPred(test)) activity data of the test set:
- vi)
- Modified R2 (R2m(test)): equation determining the proximity between the observed and predicted values with the zero axis intersection:
4.3. Searching for More Potent Indolin−2-one FLT3 Inhibitors
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Compound | Chemical Structure | IC50 (nM) FLT3 | pIC50 FLT3 |
---|---|---|---|
1 | 0.5 | 9.301 | |
2 | 1.3 | 8.886 | |
3 | 1.4 | 8.854 | |
4* | 1.6 | 8.796 | |
5* | 2.4 | 8.620 | |
6* | 2.7 | 8.569 | |
7 | 2.7 | 8.569 | |
8 | 2.7 | 8.569 | |
9 | 2.9 | 8.538 | |
10 | 2.9 | 8.538 | |
11 | 3.5 | 8.456 | |
12 | 4.4 | 8.357 | |
13* | 4.8 | 8.319 | |
14* | 6.1 | 8.215 | |
15 | 7.3 | 8.137 | |
16* | 8.1 | 8.092 | |
17 | 8.6 | 8.066 | |
18 | 10.0 | 8.000 | |
19* | 10.0 | 8.000 | |
20 | 10.3 | 7.987 | |
21 | 11.6 | 7.936 | |
22* | 15.4 | 7.812 | |
23 | 16.2 | 7.790 | |
24 | 24.6 | 7.609 | |
25 | 24.9 | 7.604 | |
26 | 27.7 | 7.558 | |
27 | 31.7 | 7.499 | |
28 | 34.9 | 7.457 | |
29 | 37.5 | 7.426 | |
30 | 37.9 | 7.421 | |
31* | 38.1 | 7.419 | |
32 | 39.4 | 7.404 | |
33 | 45.7 | 7.340 | |
34* | 48.4 | 7.315 | |
35 | 54.2 | 7.266 | |
36 | 64.2 | 7.192 | |
37 | 74.1 | 7.130 | |
38* | 86.6 | 7.062 | |
39* | 115.3 | 6.938 | |
40 | 148.4 | 6.828 | |
Quizartinib | 4.2 a1 1.1 a2 | 8.377 8.959 | |
Sunitinib | 9.9 a1 34.0 a2 | 8.004 7.468 |
Cpd/aa | Ala 642 | Asp 698 | Asp 829 | Cys 694 | Cys 695 | Cys 828 | Glu 661 | Glu 692 | Gly 697 | Leu 616 | Leu 818 | Lys 644 | Met 665 | Phe 691 | Phe 830 | Tyr 693 | Tyr 696 | Val 624 | Val 675 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | −1.90 | −1.91 | −28.29 | −12.11 | −3.75 | −18.82 | −10.10 | −4.10 | −10.57 | −23.07 | −11.32 | −1.91 | 4.22 | −14.37 | −8.25 | −14.65 | −4.19 | −3.53 | −10.21 |
2 | −3.47 | −2.52 | −8.60 | −11.61 | −3.78 | −8.46 | 11.60 | −4.30 | −9.89 | −23.55 | −12.07 | −9.62 | 70.68 | −12.02 | −8.44 | −12.14 | −3.83 | −5.74 | −7.10 |
3 | −3.18 | −2.03 | −14.63 | −10.25 | −8.59 | −8.33 | −21.14 | −1.75 | −10.32 | −21.16 | −13.13 | −1.05 | 27.99 | −12.19 | −9.04 | −13.02 | −10.30 | −4.48 | −4.60 |
4 | −2.06 | −1.81 | −12.19 | −11.28 | −8.05 | −9.41 | −15.47 | −1.70 | −9.61 | −16.22 | −14.06 | −3.23 | 1.95 | −4.00 | −12.28 | −13.12 | −6.78 | −5.76 | −8.14 |
5 | −3.93 | −4.79 | −28.56 | −10.96 | −3.05 | −24.34 | −7.84 | −4.92 | −11.72 | −14.22 | −12.61 | −2.69 | 2.79 | −14.80 | −9.70 | −10.11 | −5.02 | −5.04 | −8.56 |
6 | −3.72 | −3.25 | −19.77 | −12.07 | −2.87 | −21.27 | −4.86 | −4.94 | −9.70 | −24.01 | −11.81 | −2.57 | 7.50 | −12.93 | −8.96 | −10.96 | −2.66 | −5.69 | −10.26 |
7 | −3.58 | −5.82 | −9.43 | −12.55 | −3.54 | −10.52 | 0.52 | −2.20 | −10.90 | −17.27 | −11.75 | −7.18 | 77.63 | −8.56 | −7.08 | −10.75 | −6.27 | −5.58 | −4.75 |
8 | −4.03 | −5.13 | −15.80 | −12.87 | −2.02 | −23.44 | −2.34 | −5.47 | −8.53 | −20.14 | −12.68 | −1.61 | 9.50 | −14.83 | −8.84 | −9.66 | −2.13 | −5.05 | −7.23 |
9 | −5.14 | −2.17 | −11.28 | −8.87 | −3.82 | −6.94 | 3.47 | −3.14 | −10.13 | −18.14 | −9.58 | −6.53 | 65.61 | −12.54 | −7.25 | −11.71 | −4.78 | −8.17 | −5.69 |
10 | −2.30 | −1.62 | −12.27 | −11.99 | −3.68 | −12.31 | −9.30 | −5.20 | −9.17 | −21.41 | −11.99 | −4.35 | 38.66 | −3.53 | −7.94 | −12.27 | −3.17 | −3.58 | −8.62 |
11 | −2.39 | −1.70 | −13.05 | −12.58 | −9.24 | −10.14 | −16.87 | −2.00 | −9.45 | −11.96 | −14.02 | −2.97 | 3.85 | −2.70 | −11.56 | −15.15 | −7.67 | −5.44 | −8.52 |
12 | −3.22 | −9.77 | −17.90 | −10.84 | −4.04 | −11.92 | −25.33 | −3.83 | −15.35 | −15.56 | −12.73 | −4.41 | 15.24 | −14.71 | −9.85 | −10.81 | −7.82 | −5.72 | −6.56 |
13 | −1.79 | −1.59 | −13.55 | −10.83 | −6.14 | −11.91 | −8.55 | −2.41 | −9.81 | −15.30 | −13.45 | −5.53 | −4.10 | −2.98 | −10.12 | −15.00 | −6.59 | −5.87 | −7.99 |
14 | −2.15 | −1.80 | −25.45 | −12.12 | −3.52 | −19.77 | −8.72 | −5.03 | −9.32 | −21.43 | −11.89 | −1.71 | 3.03 | −16.56 | −8.81 | −12.82 | −3.25 | −3.42 | −7.48 |
15 | −2.66 | −2.27 | −10.52 | −12.48 | −4.21 | −10.40 | −1.77 | −3.69 | −10.22 | −24.67 | −12.05 | −6.20 | 54.98 | −1.02 | −7.62 | −11.22 | −4.02 | −3.64 | −8.03 |
16 | −2.23 | −1.92 | −13.13 | −13.07 | −3.91 | −10.60 | −1.06 | −4.51 | −10.82 | −17.85 | −11.47 | −5.12 | 39.50 | −7.34 | −7.64 | −11.77 | −4.50 | −3.50 | −9.17 |
17 | −3.33 | -0.91 | −15.54 | −14.26 | −2.48 | −12.12 | 8.11 | −4.44 | −6.15 | −12.24 | −11.87 | −7.22 | 34.52 | −3.82 | −6.98 | −12.19 | −1.25 | −5.27 | −7.94 |
18 | −3.48 | −5.04 | −20.27 | −11.13 | −2.16 | −12.32 | 44.19 | −1.95 | −9.89 | −22.54 | −10.40 | −2.13 | −2.50 | −18.51 | −11.80 | −7.48 | −2.21 | −4.43 | −7.12 |
19 | −2.15 | −1.32 | −25.70 | −14.60 | −2.07 | −18.54 | −9.08 | −6.09 | −6.94 | −17.34 | −11.95 | −2.47 | 2.22 | −16.83 | −7.05 | −12.42 | −1.64 | −4.73 | −9.06 |
20 | −2.94 | −1.97 | −12.01 | −12.66 | −6.93 | −11.42 | −17.81 | −4.69 | −14.44 | −16.58 | −10.88 | -0.31 | 33.24 | −20.81 | −8.59 | −11.82 | −14.06 | −2.89 | 5.41 |
21 | −1.80 | −1.48 | −10.81 | −11.82 | −7.05 | −11.32 | −12.80 | −1.94 | −6.00 | −19.99 | −13.32 | −4.11 | -0.97 | −3.64 | −11.52 | −6.08 | −3.90 | −6.15 | −7.82 |
22 | −1.70 | −1.31 | −12.20 | −14.35 | −1.81 | −23.16 | −2.52 | −6.30 | −4.04 | −10.48 | −11.75 | −2.02 | 8.27 | −13.68 | −6.37 | −10.84 | −1.64 | −5.55 | −6.99 |
23 | −2.59 | −1.66 | −18.36 | −11.64 | −3.54 | −12.63 | 32.16 | −3.09 | −9.04 | −13.48 | −12.99 | −7.69 | −2.75 | −19.03 | −8.37 | −14.20 | −3.84 | −3.67 | −8.31 |
24 | −4.49 | −2.12 | −13.80 | −9.24 | −3.64 | −11.07 | 7.10 | −3.21 | −10.41 | −18.62 | −11.74 | −9.56 | 27.49 | −10.24 | −8.61 | −11.81 | −4.27 | −6.65 | −7.45 |
25 | −4.44 | −1.16 | −23.81 | −11.81 | −3.31 | −11.65 | 2.30 | −2.16 | −4.03 | −10.48 | −12.26 | −8.10 | −1.23 | 11.81 | −8.98 | −11.76 | −2.85 | −6.58 | −8.21 |
26 | −3.46 | −1.01 | −17.06 | −12.26 | −2.70 | −15.76 | 5.74 | −1.79 | −5.98 | −10.60 | −12.48 | −3.40 | 50.76 | −13.89 | −7.20 | −10.54 | −2.08 | −6.03 | −1.60 |
27 | −3.04 | −1.25 | −21.42 | −10.60 | −3.94 | −11.96 | −21.37 | −4.68 | −8.62 | −15.67 | −11.82 | −4.61 | −1.05 | −14.40 | −9.63 | −16.59 | −3.29 | −6.16 | −7.27 |
28 | −1.88 | −1.12 | −16.49 | −8.57 | −6.61 | −10.78 | −7.95 | -0.93 | −7.19 | −21.41 | −10.72 | −6.68 | 4.37 | 0.54 | −9.77 | −12.12 | −4.89 | −8.58 | −7.27 |
29 | −2.58 | -0.85 | −19.75 | −12.76 | −3.21 | −10.32 | 12.68 | −1.89 | −6.22 | −13.12 | −11.82 | −4.08 | 29.51 | −12.09 | −6.24 | −12.57 | −2.05 | −6.41 | −4.56 |
30 | −1.89 | -0.79 | −14.09 | −13.14 | −2.10 | −11.77 | −6.60 | −5.49 | −5.51 | −5.58 | −12.82 | −4.48 | −4.64 | −8.71 | −11.04 | −11.76 | −1.12 | −4.29 | −7.49 |
31 | −3.00 | -0.67 | −20.12 | −13.76 | −2.70 | −11.78 | −4.00 | −4.92 | −5.82 | −10.84 | −11.69 | −6.47 | −2.56 | 5.56 | −7.77 | −12.88 | −1.14 | −5.24 | −8.90 |
32 | −3.59 | −2.33 | −17.04 | −10.53 | −4.09 | −15.48 | −15.18 | −1.60 | −10.97 | −18.08 | −11.57 | −1.90 | 6.44 | −16.41 | −8.20 | −9.10 | −5.18 | −7.44 | 4.76 |
33 | −2.96 | −2.01 | −14.00 | −11.59 | −3.68 | −12.27 | −21.55 | −3.87 | −10.00 | −19.56 | −12.71 | −3.81 | 21.37 | −16.47 | −8.23 | −12.49 | −4.03 | −4.28 | −5.11 |
34 | −2.04 | −1.24 | −14.85 | −14.31 | −2.46 | −12.11 | 6.84 | −5.96 | −5.13 | −8.97 | −12.32 | −5.81 | 27.07 | −12.89 | −6.44 | −11.51 | −1.79 | −4.35 | −8.87 |
35 | −2.42 | −1.55 | −25.07 | −11.15 | −9.38 | −18.03 | −8.01 | −2.73 | -0.36 | −13.27 | −12.19 | −1.68 | −2.38 | −15.94 | −7.62 | −16.61 | −6.66 | −4.76 | −4.90 |
36 | −2.07 | −1.14 | −14.32 | −14.53 | −1.87 | −11.28 | 10.54 | −5.39 | −5.15 | −8.90 | −12.44 | −7.02 | 2.20 | −10.78 | −7.14 | −10.95 | −1.30 | −4.78 | −8.37 |
37 | −2.23 | −1.22 | −17.23 | −14.97 | −1.41 | −20.78 | −5.56 | −6.80 | −5.08 | −10.34 | −12.09 | −2.18 | 4.18 | −17.93 | −6.69 | −10.49 | −1.07 | −4.24 | -0.69 |
38 | −2.24 | −1.51 | −14.39 | −10.47 | −3.64 | −11.66 | −8.32 | −5.08 | −8.20 | −11.91 | −12.40 | −4.53 | −4.61 | −5.64 | −9.53 | −11.34 | −2.65 | −3.94 | −7.51 |
39 | −3.53 | −2.64 | −19.41 | −8.51 | −2.35 | −17.95 | −11.74 | −1.44 | −9.49 | −17.55 | −10.16 | −1.61 | 8.11 | −16.42 | −13.80 | −6.79 | −3.21 | −8.19 | 2.66 |
40 | −2.77 | -0.98 | −22.08 | −12.72 | −3.36 | −7.88 | 4.48 | −1.86 | −6.34 | −12.98 | −12.08 | −4.22 | −1.32 | −10.22 | −5.81 | −12.47 | −2.26 | −6.27 | −7.50 |
Quiz | −4.48 | −1.55 | −18.63 | −8.59 | −7.63 | −19.56 | −11.13 | −1.64 | −10.93 | −15.17 | −9.37 | −4.92 | 2.19 | −9.99 | −12.34 | −10.03 | −13.10 | −7.47 | −6.01 |
Sunit | −2.11 | −1.65 | −2.84 | −10.80 | −8.63 | −0.98 | - | −3.42 | −9.61 | −19.49 | −12.80 | - | - | −4.01 | −10.82 | −16.27 | −19.13 | −5.61 | −3.63 |
Parameters | Accept Values | Obtained Values |
---|---|---|
R2 | >0.8 | 0.80 |
RMSEc | - | 0.29 |
q2 | >0.5 | 0.60 |
RMSEcv | - | 0.46 |
LV | - | 5 |
R2rand | < r2 | 0.22 |
RMSE y-rand | - | 0.60 |
R2pred | >0.8 | 0.80 |
RMSEpred | - | 0.31 |
r2m(test) | >0.5 | 0.68 |
R2p | >0.5 | 0.61 |
Compd | Chemical Structure | pIC50 pred | MolDock Score | Inter Energy | H Bond Energy |
---|---|---|---|---|---|
IAF70 | 10.06 | −236.96 | −249.26 | −9.37 | |
IAF72 | 10.25 | −238.17 | −251.73 | −6.74 | |
IAF75 | 10.24 | −257.27 | −254.38 | −13.95 | |
IAF80 | 10.22 | −255.22 | −252.98 | −11.75 | |
IAF84 | 10.13 | −261.42 | −258.18 | −11.16 | |
IAF88 | 10.12 | −254.29 | −250.82 | −8.30 |
Compd | Chemical Structure | Enzyme | pIC50 pred | MolDock Score | Inter Energy | H Bond Energy |
---|---|---|---|---|---|---|
IAF79 | Aurora B | 11.39 b | −236.71 b | −240.59 b | −15.61 b | |
FLT3 | 9.83 | −248.06 | −246.77 | −8.35 |
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Fernandes, Í.A.; Braga Resende, D.; Ramalho, T.C.; Kuca, K.; da Cunha, E.F.F. Theoretical Studies Aimed at Finding FLT3 Inhibitors and a Promising Compound and Molecular Pattern with Dual Aurora B/FLT3 Activity. Molecules 2020, 25, 1726. https://doi.org/10.3390/molecules25071726
Fernandes ÍA, Braga Resende D, Ramalho TC, Kuca K, da Cunha EFF. Theoretical Studies Aimed at Finding FLT3 Inhibitors and a Promising Compound and Molecular Pattern with Dual Aurora B/FLT3 Activity. Molecules. 2020; 25(7):1726. https://doi.org/10.3390/molecules25071726
Chicago/Turabian StyleFernandes, Ítalo Antônio, Déborah Braga Resende, Teodorico Castro Ramalho, Kamil Kuca, and Elaine Fontes Ferreira da Cunha. 2020. "Theoretical Studies Aimed at Finding FLT3 Inhibitors and a Promising Compound and Molecular Pattern with Dual Aurora B/FLT3 Activity" Molecules 25, no. 7: 1726. https://doi.org/10.3390/molecules25071726