Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation
Abstract
1. Introduction
2. Results
2.1. Molecular Modeling
2.2. Molecular Docking
3. Discussion
4. Materials and Methods
4.1. Molecular Modeling
4.1.1. Energy Optimization of Isosteviol Analogues
Compound | Sample | R * | Optimized Molecular Structure | Inhibition Constant (Ki), µM ** |
---|---|---|---|---|
a | train | 9.253 | ||
b | train | 4.333 | ||
d | train | 9.786 | ||
e | train | 2.693 | ||
f | train | 1.023 | ||
g | train | 0.321 | ||
h | test | 9.877 | ||
i | train | 0.515 | ||
j | test | 1.941 | ||
k | train | 0.015 | ||
l | train | 4.025 | ||
m | train | 2.875 | ||
n | train | 1.809 | ||
o | train | 1.612 | ||
p | validation | 0.028 | ||
q | train | 0.785 | ||
r | validation | 8.607 |
4.1.2. Molecular Descriptors
4.1.3. Regression Analysis
4.2. Molecular Docking Study
5. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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MLP 5-8-1 Model | |
---|---|
Learning algorithm | BFGS 31 |
Activation function (Hidden layer) | Logistic |
Activation function (Output layer) | Tanh |
Name | Definition | Category | Dimensionality | Error MLP 5-8-1 | Rank |
---|---|---|---|---|---|
GATS8p | Geary autocorrelation of lag 8 weighted by polarizability [19] | 2D autocorrelations | 2D | 16.75531 | 1 |
HATS2i | leverage-weighted autocorrelation of lag 2/weighted by ionization potential [19] | GETAWAY descriptors | 3D | 14.49011 | 2 |
R5e | R autocorrelation of lag 5/weighted by Sanderson electronegativity [19] | GETAWAY descriptors | 3D | 13.33332 | 3 |
HATS2e | leverage-weighted autocorrelation of lag 2/weighted by Sanderson electronegativity [19] | GETAWAY descriptors | 3D | 8.866242 | 4 |
SpMAD_B(v) | spectral mean absolute deviation from Burden matrix weighted by van der Waals volume [19] | 2D-matrix-based descriptors | 2D | 8.699860 | 5 |
Compound | R * | Predicted Inhibition Activity Against FXa: Inhibition Constant (Ki), [µM] ** |
---|---|---|
e1 | 9.785990 | |
e2 | 1.118201 | |
e3 | 0.645249 | |
e4 | 9.282278 | |
e5 | 3.984843 | |
e6 | 6.454281 | |
e7 | 2.640193 | |
e8 | 1.421969 | |
e9 | 4.412301 | |
e10 | 1.569841 | |
e11 | 1.133094 | |
e12 | 0.936761 | |
e13 | 0.372101 | |
e14 | 0.544725 | |
e15 | 0.906731 | |
e16 | 0.947983 | |
e17 | 0.936441 | |
e18 | 0.650819 | |
e19 | 0.493827 | |
e20 | 0.673789 | |
e21 | 0.656182 | |
e22 | 0.749590 | |
e23 | 0.554588 | |
e24 | 0.642575 | |
e25 | 0.687738 | |
e26 | 0.854700 |
Compound | Binding-Free Energy (kcal/mol) |
---|---|
a | −8.7 |
b | −8.3 |
d | −9.3 |
e | −8.1 |
f | −8.8 |
g | −8.3 |
h | −8.4 |
i | −7.4 |
j | −8.0 |
k | −8.1 |
l | −8.7 |
m | −7.8 |
n | −6.9 |
o | −7.7 |
p | −7.0 |
q | −8.0 |
r | −6.8 |
e1 | −6.9 |
e2 | −7.7 |
e3 | −8.0 |
e4 | −7.4 |
e5 | −7.2 |
e6 | −7.1 |
e7 | −7.4 |
e8 | −7.4 |
e9 | −7.5 |
e10 | −7.6 |
e11 | −7.3 |
e12 | −7.7 |
e13 | −7.7 |
e14 | −7.2 |
e15 | −8.3 |
e16 | −6.9 |
e17 | −7.7 |
e18 | −7.4 |
e19 | −6.9 |
e20 | −8.1 |
e21 | −8.3 |
e22 | −7.0 |
e23 | −8.1 |
e24 | −8.2 |
e25 | −8.2 |
e26 | −7.0 |
apixaban | −10.3 |
edoxaban | −8.8 |
rivaroxaban | −9.4 |
Action | Reason | Number |
---|---|---|
deleted | constant | 1856 |
near constant | 95 | |
all missing | 2 | |
one missing | 2 | |
highly correlated (|r| > 0.95) | 1658 | |
standard deviation < 0.0001 | 1856 | |
retained | suitable for model-building | 1274 |
Symbol | Variable Rank | Importance |
---|---|---|
GATS8p | 100 | 1 |
R5e | 100 | 1 |
HATS2i | 100 | 1 |
HATS2e | 100 | 1 |
SpMAD_B(v) | 100 | 1 |
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Gackowski, M.; Madriwala, B.; Studzińska, R.; Koba, M. Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation. Molecules 2023, 28, 4977. https://doi.org/10.3390/molecules28134977
Gackowski M, Madriwala B, Studzińska R, Koba M. Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation. Molecules. 2023; 28(13):4977. https://doi.org/10.3390/molecules28134977
Chicago/Turabian StyleGackowski, Marcin, Burhanuddin Madriwala, Renata Studzińska, and Marcin Koba. 2023. "Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation" Molecules 28, no. 13: 4977. https://doi.org/10.3390/molecules28134977
APA StyleGackowski, M., Madriwala, B., Studzińska, R., & Koba, M. (2023). Novel Isosteviol-Based FXa Inhibitors: Molecular Modeling, In Silico Design and Docking Simulation. Molecules, 28(13), 4977. https://doi.org/10.3390/molecules28134977