Novel Autotaxin Inhibitor ATX-1d Significantly Enhances Potency of Paclitaxel—An In Silico and In Vitro Study
Abstract
:1. Introduction
2. Methods
3. Computational Details
3.1. Molecular Docking
3.2. Molecular Dynamics (MD) Simulations
3.3. Binding Free Energy Calculations
3.4. QM/MM-GBSA Calculations
3.5. Symmetry-Adapted Perturbation Theory (SAPT) Calculations
3.6. Conceptual DFT Parameters
4. Experimental Details
4.1. Chemical Samples
4.2. In Vitro ATX Enzyme Inhibition Assay
4.3. Cell Viability Assay
5. Results and Discussion
5.1. Molecular Docking
5.2. In Vitro Screening through ATX Enzyme Inhibition Assay
5.3. MD Simulations
5.4. SAPT Calculations
5.5. Cellular Activity of ATX-1d
5.6. ATX Inhibition by ATX-1d Improves Cellular Response to PTX
5.7. Conceptual DFT Parameters
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Residues | van der Waals | Electrostatic | Polar Solv. | Non-Polar Solv. | TOTAL | |||||
---|---|---|---|---|---|---|---|---|---|---|
Avg. | Std. Err. of Mean | Avg. | Std. Err. of Mean | Avg. | Std. Err. of Mean | Avg. | Std. Err. of Mean | Avg. | Std. Err. of Mean | |
GLN:67 | −0.09 | 0.00 | −0.46 | 0.00 | 0.45 | 0.00 | −0.04 | 0.00 | −0.14 | 0.00 |
LEU:79 | −1.29 | 0.01 | 0.06 | 0.00 | −0.21 | 0.00 | −1.22 | 0.00 | −2.66 | 0.01 |
SER:82 | −0.47 | 0.00 | −0.06 | 0.00 | −0.08 | 0.00 | −0.43 | 0.00 | −1.03 | 0.01 |
TYR:83 | −0.78 | 0.01 | −0.55 | 0.01 | 0.13 | 0.00 | −0.65 | 0.01 | −1.85 | 0.02 |
PHE:211 | −1.52 | 0.01 | −0.39 | 0.00 | 0.11 | 0.00 | −1.33 | 0.01 | −3.13 | 0.01 |
TYR:215 | −0.93 | 0.01 | −0.20 | 0.00 | 0.02 | 0.00 | −0.72 | 0.00 | −1.83 | 0.01 |
LEU:244 | −0.74 | 0.00 | 0.21 | 0.00 | −0.26 | 0.00 | −0.70 | 0.00 | −1.48 | 0.01 |
ARG:245 | −0.09 | 0.00 | 0.20 | 0.00 | −0.20 | 0.00 | 0.00 | 0.00 | −0.10 | 0.01 |
LYS:249 | −1.83 | 0.00 | −5.32 | 0.03 | 4.15 | 0.02 | −1.54 | 0.00 | −4.53 | 0.03 |
PHE:250 | −1.78 | 0.00 | −0.27 | 0.00 | 0.17 | 0.00 | −1.45 | 0.00 | −3.34 | 0.01 |
TRP:255 | −2.63 | 0.01 | −0.60 | 0.00 | −0.13 | 0.00 | −1.92 | 0.01 | −5.28 | 0.01 |
TRP:261 | −1.43 | 0.01 | −0.10 | 0.00 | −0.09 | 0.00 | −1.25 | 0.00 | −2.86 | 0.01 |
ILE:262 | −0.26 | 0.00 | 0.00 | 0.00 | 0.01 | 0.00 | −0.22 | 0.00 | −0.46 | 0.00 |
THR:273 | −0.18 | 0.00 | −0.02 | 0.00 | 0.10 | 0.00 | −0.15 | 0.00 | −0.25 | 0.00 |
PHE:274 | −0.41 | 0.00 | −0.08 | 0.00 | 0.06 | 0.00 | −0.18 | 0.00 | −0.60 | 0.00 |
PHE:275 | −2.44 | 0.01 | −0.66 | 0.00 | 0.06 | 0.00 | −2.02 | 0.00 | −5.06 | 0.01 |
Compounds | van der Waals | Electrostatics (SCF) | Polar Solv. | Non-Polar Solv. | TOTAL | |||||
---|---|---|---|---|---|---|---|---|---|---|
Avg. | Std. Err. of Mean | Avg. | Std. Err. of Mean | Avg. | Std. Err. of Mean | Avg. | Std. Err. of Mean | Avg. | Std. Err. of Mean | |
SKV (native ligand, PDB ID: 6W35) vs. ATX | −5.85 | 0.01 | −68.09 | 0.11 | 58.78 | 0.11 | −7.79 | 0.01 | −22.95 | 0.06 |
ATX−1d vs. ATX | −7.06 | 0.06 | −65.58 | 0.43 | 69.86 | 0.46 | −5.6 | 0.02 | −8.37 | 0.11 |
Compounds | Total SAPT0 Protein–Ligand Interaction Energy (in kcal/mol) |
---|---|
SKV (native ligand, PDB ID: 6W35) vs. ATX | −65.80 |
ATX-1d vs. ATX | −49.78 |
4T1 Breast Cancer Cells | A375 Melanoma Cells | ||
---|---|---|---|
Compounds | GI50 (in nM) | Compounds | GI50 (in nM) |
Paclitaxel | 62 ± 18 | Paclitaxel | 4 ± 1 |
ATX-1d | >20,000 | ATX-1d | >20,000 |
Compound | ATX−1d |
---|---|
ELUMO | −0.041 |
EHOMO | −0.299 |
Energy Gap (Eg) {Eg = ELUMO − EHOMO} | 0.258 |
Ionization Potential (IP) {IP = −EHOMO} | 0.299 |
Electron Affinity (EA) {EA = −ELUMO} | 0.041 |
Electronegativity (χ) {χ = | 0.170 |
Chemical Potential (μ) {μ = | −0.170 |
Global Hardness (η) {η = } | 0.129 |
Global Softness (S) {S = } | 3.875 |
Electrophilicity Index (ω) {ω = } | 0.112 |
Nucleophilicity Index (ε) {ε = } | 8.964 |
Maximum Charge Transfer Index (ΔNmax) {ΔNmax = } | 1.315 |
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Rai, P.; Clark, C.J.; Womack, C.B.; Dearing, C.; Thammathong, J.; Norman, D.D.; Tigyi, G.J.; Sen, S.; Bicker, K.; Weissmiller, A.M.; et al. Novel Autotaxin Inhibitor ATX-1d Significantly Enhances Potency of Paclitaxel—An In Silico and In Vitro Study. Molecules 2024, 29, 4285. https://doi.org/10.3390/molecules29184285
Rai P, Clark CJ, Womack CB, Dearing C, Thammathong J, Norman DD, Tigyi GJ, Sen S, Bicker K, Weissmiller AM, et al. Novel Autotaxin Inhibitor ATX-1d Significantly Enhances Potency of Paclitaxel—An In Silico and In Vitro Study. Molecules. 2024; 29(18):4285. https://doi.org/10.3390/molecules29184285
Chicago/Turabian StyleRai, Prateek, Christopher J. Clark, Carl B. Womack, Curtis Dearing, Joshua Thammathong, Derek D. Norman, Gábor J. Tigyi, Subhabrata Sen, Kevin Bicker, April M. Weissmiller, and et al. 2024. "Novel Autotaxin Inhibitor ATX-1d Significantly Enhances Potency of Paclitaxel—An In Silico and In Vitro Study" Molecules 29, no. 18: 4285. https://doi.org/10.3390/molecules29184285