Investigation of Potential cGMP-Specific PDE V and Aminopeptidase N Inhibitors of Allium ampeloprasum L. and Its Bioactive Components: Kinetic and Molecular Docking Studies
Abstract
:1. Introduction
2. Results
2.1. Effects of AAE, DATS, DADS, KAE, QUE, MT, and IA on PDE5 Activity
2.2. Effects of AAE, DATS, DADS, KAE, QUE, MT, and IA on APN Activity
2.3. Effects of AAE, DATS, DADS, KAE, QUE, MT, and IA on Kinetic Parameters of Enzymes
2.4. In Silico Molecular Docking Analysis
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Extraction of Allium ampeloprasum L.
4.3. cGMP-Specific PDE V Assay
4.4. Aminopeptidase N Assay
4.5. Kinetic Assay
4.6. Molecular Docking
4.7. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Km (mM) | Vmax (mU/min) | Kcat (k s−1) | Ki | Kik | Kiv | Kik/Kiv | |
---|---|---|---|---|---|---|---|---|
Non-treated | 0.223 ± 0.013 | 1.039 ± 0.052 | 7858 ± 393 | - | - | - | - | |
AAE (mg) | 0.01 | 0.199 ± 0.011 | 0.899 ± 0.033 | 6795 ± 249 | 0.084 mg | 0.437 | 0.065 | 6.8 |
0.02 | 0.201 ± 0.015 | 0.849 ± 0.028 | 6415 ± 212 | |||||
0.05 | 0.168 ± 0.011 | 0.646 ± 0.021 | 4887 ± 159 | |||||
0.1 | 0.182 ± 0.012 | 0.408 ± 0.020 | 3085 ± 151 | |||||
DATS (mM) | 1 | 0.211 ± 0.012 | 0.940 ± 0.026 | 7105 ± 197 | 7.53 mM | 133.4 | 7.51 | 17.8 |
2 | 0.206 ± 0.014 | 0.894 ± 0.032 | 6757 ± 242 | |||||
5 | 0.221 ± 0.011 | 0.655 ± 0.023 | 4955 ± 174 | |||||
10 | 0.208 ± 0.009 | 0.446 ± 0.019 | 3371 ± 144 | |||||
DADS (mM) | 1 | 0.208 ± 0.010 | 0.959 ± 0.025 | 7253 ± 189 | 13.53 mM | 201.9 | 12.61 | 16.0 |
2 | 0.211 ± 0.013 | 0.876 ± 0.021 | 6625 ± 159 | |||||
5 | 0.198 ± 0.013 | 0.781 ± 0.011 | 5905 ± 83 | |||||
10 | 0.213 ± 0.012 | 0.580 ± 0.010 | 4383 ± 76 | |||||
KAE (mM) | 1 | 0.215 ± 0.009 | 0.671 ± 0.013 | 5076 ± 98 | 3.61 mM | 16.92 | 1.85 | 9.1 |
2 | 0.214 ± 0.008 | 0.607 ± 0.010 | 4591 ± 76 | |||||
5 | 0.153 ± 0.011 | 0.316 ± 0.016 | 2390 ± 121 | |||||
10 | 0.140 ± 0.007 | 0.162 ± 0.009 | 1228 ± 69 | |||||
QUE (mM) | 1 | 0.224 ± 0.016 | 0.724 ± 0.031 | 5473 ± 234 | 4.05 mM | 21.80 | 2.32 | 9.4 |
2 | 0.221 ± 0.011 | 0.686 ± 0.022 | 5187 ± 166 | |||||
5 | 0.184 ± 0.015 | 0.383 ± 0.008 | 2893 ± 60 | |||||
10 | 0.153 ± 0.009 | 0.195 ± 0.005 | 1478 ± 38 | |||||
MT (mM) | 1 | 0.215 ± 0.010 | 0.828 ± 0.025 | 6261 ± 189 | 21.46 mM | 28.02 | 8.78 | 3.2 |
2 | 0.203 ± 0.014 | 0.738 ± 0.021 | 5580 ± 159 | |||||
5 | 0.174 ± 0.014 | 0.530 ± 0.013 | 4007 ± 98 | |||||
10 | 0.165 ± 0.011 | 0.486 ± 0.019 | 3673 ± 144 | |||||
IA (mM) | 1 | 0.219 ± 0.012 | 0.871 ± 0.021 | 6587 ± 159 | 10.80 mM | 136.3 | 10.46 | 13.0 |
2 | 0.238 ± 0.015 | 0.726 ± 0.020 | 5489 ± 151 | |||||
5 | 0.230 ± 0.013 | 0.580 ± 0.017 | 4387 ± 129 | |||||
10 | 0.240 ± 0.011 | 0.531 ± 0.015 | 4018 ± 114 |
Compound | Km (mM) | Vmax (mU/min) | Kcat (s−1) | Ki | Kik | Kiv | Kik/Kiv | |
---|---|---|---|---|---|---|---|---|
Non-treated | 0.427 ± 0.017 | 0.316 ± 0.011 | 392.0 ± 13.6 | - | - | - | - | |
AAE (mg) | 0.01 | 0.763 ± 0.026 | 0.254 ± 0.005 | 315.5 ± 6.2 | 0.057 mg | 0.108 | 0.066 | 1.6 |
0.02 | 0.884 ± 0.025 | 0.194 ± 0.006 | 240.3 ± 7.4 | |||||
0.05 | 0.840 ± 0.021 | 0.171 ± 0.003 | 212.4 ± 3.7 | |||||
0.1 | 0.822 ± 0.020 | 0.126 ± 0.003 | 156.3 ± 3.7 | |||||
DATS (mM) | 1 | 0.422 ± 0.012 | 0.297 ± 0.006 | 368.9 ± 7.4 | 18.74 mM | 0.685 | 0.269 | 2.5 |
2 | 0.499 ± 0.014 | 0.294 ± 0.005 | 365.3 ± 6.2 | |||||
5 | 0.466 ± 0.015 | 0.249 ± 0.004 | 309.2 ± 5.0 | |||||
10 | 0.489 ± 0.011 | 0.230 ± 0.004 | 285.9 ± 5.0 | |||||
DADS (mM) | 1 | 0.439 ± 0.013 | 0.318 ± 0.003 | 394.8 ± 3.7 | 65.71 mM | 1.369 | 1.250 | 1.1 |
2 | 0.437 ± 0.016 | 0.306 ± 0.006 | 379.5 ± 7.4 | |||||
5 | 0.440 ± 0.012 | 0.297 ± 0.005 | 368.8 ± 6.2 | |||||
10 | 0.461 ± 0.015 | 0.294 ± 0.004 | 364.9 ± 5.0 | |||||
KAE (mM) | 1 | 0.441 ± 0.015 | 0.319 ± 0.006 | 396.3 ± 7.5 | 11.94 mM | 0.421 | 0.217 | 1.9 |
2 | 0.478 ± 0.011 | 0.284 ± 0.006 | 352.8 ± 7.4 | |||||
5 | 0.563 ± 0.013 | 0.248 ± 0.004 | 308.0 ± 5.0 | |||||
10 | 0.528 ± 0.014 | 0.216 ± 0.003 | 268.5 ± 3.7 | |||||
QUE (mM) | 1 | 0.430 ± 0.011 | 0.297 ± 0.005 | 368.1 ± 6.2 | 13.19 mM | 3.272 | 0.118 | 27.7 |
2 | 0.442 ± 0.009 | 0.255 ± 0.006 | 316.6 ± 7.4 | |||||
5 | 0.415 ± 0.010 | 0.197 ± 0.003 | 244.1 ± 3.7 | |||||
10 | 0.414 ± 0.013 | 0.171 ± 0.002 | 212.3 ± 2.5 | |||||
MT (mM) | 1 | 0.419 ± 0.012 | 0.296 ± 0.003 | 367.0 ± 3.7 | 13.43 mM | 3.428 | 0.126 | 27.1 |
2 | 0.411 ± 0.007 | 0.250 ± 0.005 | 310.6 ± 6.2 | |||||
5 | 0.407 ± 0.009 | 0.199 ± 0.003 | 246.8 ± 3.7 | |||||
10 | 0.415 ± 0.010 | 0.176 ± 0.002 | 218.9 ± 2.5 | |||||
IA (mM) | 1 | 0.430 ± 0.011 | 0.307 ± 0.005 | 381.3 ± 6.2 | 33.08 mM | 1.142 | 0.237 | 4.8 |
2 | 0.395 ± 0.009 | 0.267 ± 0.006 | 331.6 ± 7.4 | |||||
5 | 0.391 ± 0.013 | 0.241 ± 0.004 | 298.9 ± 4.9 | |||||
10 | 0.392 ± 0.010 | 0.222 ± 0.003 | 275.8 ± 3.7 |
Ligand | Van der Waals | Hydrogen Bond | Electrostatic | Hydrophobic | ||
---|---|---|---|---|---|---|
DATS | LEU540, ARG597, LEU600, LYS604 | - | Attractive charge: GLU536, GLU539 | - | - | - |
DADS | GLU536, LEU540, ARG597, LEU600, LYS604 | - | Attractive charge: GLU539 | - | - | - |
KAE | GLU536, THR537, LEU540, PRO696 | Conventional: GLU539, ARG597 | - | - | - | Pi-Alkyl: ARG597, LEU600, LYS604 |
QUE | ASN605 | Conventional: LYS603, LYS604, TYR606, LYS608 | - | Pi-Anion: GLU539, ASP568 | Pi-Cation: LYS608 | Pi-Alkyl: LYS604 |
MT | GLU536, ARG597, LEU600, SER601, LYS604, ASN698 | Conventional: GLU539 | Attractive charge: GLU539 | - | - | - |
IA | GLU536, LEU540, ARG597, LEU600, SER601, LYS604, ASN698 | - | Attractive charge: GLU539 | - | - | - |
Ligand | Van der Waals | Hydrogen Bond | Unfavorable | Electrostatic | Hydrophobic | Miscellaneous | |||
---|---|---|---|---|---|---|---|---|---|
DATS | MET260 *, GLY261 *, ASN272, TYR275, ILE751, ASN780, SER784 | - | Positive–positive: LYS274, ARG783 | - | - | - | - | - | - |
DADS | ARG349, LYS541, LEU628 | Conventional: GLU627 | - | Attractive charge: GLU543 | - | - | - | - | Pi-Sulfur: PHE353 |
KAE | LEU289, ASN343, ASN344 | Conventional: LYS286, ARG293 * Carbon hydrogen: LYS286, ARG293 *, ASN343 | - | - | Pi-Anion: ASP290 | - | Pi-Alkyl: LYS286 | - | - |
QUE | LEU289, ARG293 *, ASN344, ARG346, GLU382 | Conventional: LYS286, ASN343 Carbon hydrogen: LYS286, ARG293 *, ASN343 | - | - | Pi-Anion: ASP290 | Pi-Cation: LYS286 | - | Pi-Sigma: LYS286 | - |
MT | VAL622, THR755 | - | Positive–positive: ARG641 | - | - | - | - | - | - |
IA | ARG641, LEU752, THR755 | - | - | - | - | - | - | - | - |
Ligand | Lowest Binding Energy (kcal/mol) | Average Docking Energy (kcal/mol) |
---|---|---|
DATS | −5.6 | −5.06 (n = 10) |
DADS | −5.3 | −4.74 (n = 10) |
KAE | −7.2 | −6.6 (n = 9) |
QUE | −7.7 | −6.0 (n = 9) |
MT | −5.2 | −4.75 (n = 10) |
IA | −7.1 | −5.16 (n = 10) |
SILD | −9.4 | −8.54 (n = 9) |
Ligand | Lowest Binding Energy (kcal/mol) | Average Docking Energy (kcal/mol) |
---|---|---|
DATS | −5.4 | −4.59 (n = 10) |
DADS | −5.0 | −4.50 (n = 10) |
KAE | −8.1 | −7.59 (n = 9) |
QUE | −8.3 | −7.71 (n = 9) |
MT | −5.9 | −5.05 (n = 10) |
IA | −6.6 | −5.22 (n = 10) |
BEST | −8.3 | −7.99 (n = 9) |
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Choi, J.-H.; Park, S.-M.; Kim, S. Investigation of Potential cGMP-Specific PDE V and Aminopeptidase N Inhibitors of Allium ampeloprasum L. and Its Bioactive Components: Kinetic and Molecular Docking Studies. Int. J. Mol. Sci. 2023, 24, 13319. https://doi.org/10.3390/ijms241713319
Choi J-H, Park S-M, Kim S. Investigation of Potential cGMP-Specific PDE V and Aminopeptidase N Inhibitors of Allium ampeloprasum L. and Its Bioactive Components: Kinetic and Molecular Docking Studies. International Journal of Molecular Sciences. 2023; 24(17):13319. https://doi.org/10.3390/ijms241713319
Chicago/Turabian StyleChoi, Jun-Hui, Seung-Man Park, and Seung Kim. 2023. "Investigation of Potential cGMP-Specific PDE V and Aminopeptidase N Inhibitors of Allium ampeloprasum L. and Its Bioactive Components: Kinetic and Molecular Docking Studies" International Journal of Molecular Sciences 24, no. 17: 13319. https://doi.org/10.3390/ijms241713319