In Silico Finding of Key Interaction Mediated α3β4 and α7 Nicotinic Acetylcholine Receptor Ligand Selectivity of Quinuclidine-Triazole Chemotype
Abstract
:1. Introduction
2. Results and Discussion
2.1. nAChR Homology Model Templates (α7 and α3β4 Subtypes)
2.2. Binding Modes
2.2.1. Binding Modes of (S)-Enantiomers
2.2.2. Binding Modes of (R)-Enantiomers
2.3. Identification of Amino Acid Determinants and Interactions for the Stereoselective Binding
2.3.1. Determinants of Selective α3β4 Binding
2.3.2. Determinants of Selective α7 Binding
3. Materials and Methods
3.1. Protein Template and Ligand Preparations
3.2. Molecular docking
3.3. Molecular Dynamics (MD) Simulation
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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R | Ki in nM (Mean ± SD) 1 | Eudismic Ratio 2 | Subtype Selectivity Ratio 3 | ||||
---|---|---|---|---|---|---|---|
Cpd | α3β4 | α7 | α3β4 (S/R) | α7 (R/S) | α3β4 | α7 | |
(R)-T1 | p-F | 1010 ± 162 | 73.0 ± 15 | 2.4 | 14 | ||
(S)-T1 | 3.09 ± 0.10 | 174.5 ± 66 | 327 | 56 | |||
(R)-T2 | m-F | 362 ± 27 | 117 ± 4 | 5.7 | 3.1 | ||
(S)-T2 | 2.25 ± 0.42 | 660.5 ± 139 | 161 | 294 | |||
(R)-T3 | m-O(CH2)2F | 558 ± 34 | 38.8 ± 8 | 1.9 | 14 | ||
(S)-T3 | 11.8 ± 0.3 | 74.9 ± 20 | 47 | 6.3 | |||
(R)-T4 | m-O(CH2)3F | 1628 ± 11 | 62.3 ± 10 | 1.6 | 26 | ||
(S)-T4 | 19.5 ± 0.4 | 96.9 ± 17 | 83 | 5 | |||
(R)-T5 | m-OBn | 631 ± 206 | 22.5 ± 9 | 12 | 28 | ||
(S)-T5 | 6.67 ± 0.7 | 279 ± 31 | 95 | 42 | |||
(R)-T6 | m-OCH2C6H4-p-F | 1090 ± 163 | 33.2 ± 7 | 4.5 | 33 | ||
(S)-T6 | 7.17 ± 1.2 | 149 ± 42 | 152 | 21 |
Selected nAChR Model | Modeller Scoring Function | Ramachandran Plot | ||||
---|---|---|---|---|---|---|
DOPE Score | GA341 Score | Most Favored Region | Additional Allowed Region | Generously Allowed Region | Disallowed Region | |
α7 | −46,953.29688 | 1 | 92.3 | 6.6 | 0.5 | 0.5 |
α3β4 | −46,290.92188 | 0.99998 | 91.1 | 7.6 | 1.0 | 0.3 |
| α3β4 nAChR Interaction | α7 nAChR Interaction | ||||||
---|---|---|---|---|---|---|---|---|
Hydrogen Bond (Distance in Å) | Salt Bridge Opportunity | Cation-π | π-π | Hydrogen Bond (Distance in Å) | Cation-π | π-π | ||
Cpd | R | |||||||
(R)-T1 | p-F | TyrA93 (2.45) TyrA197 (3.02, 3.16) | - | TrpA149 TyrA197 | - | TrpA149 (1.80) | TrpA149 TyrA195 | TrpB55 |
(S)-T1 | AspB173 (1.78) | AspB173 | - | TrpA149 | TyrA93 (2.30) SerA148 (3.36) | TyrA188 TyrA195 | - | |
(R)-T2 | m-F | TyrA93 (3.36) TyrA197 (3.23, 3.36) | - | TyrA190 TyrA197 | - | TyrA93 (2.24) SerA148 (2.82) | TyrA195 | - |
(S)-T2 | AspB173 (1.77) | AspB173 | - | TrpA149 TyrA190 | TyrA93 (2.11) SerA148 (3.22) | TyrA188 TyrA195 | TrpB55 | |
(R)-T3 | m-O(CH2)2F | AspB173 (2.05) TyrA190 (2.77) | AspB173 | - | TyrA190 | TrpA149 (1.90) TyrA188 (3.01) | TrpA149 TyrA195 | - |
(S)-T3 | AspB173 (1.78) | AspB173 | - | TrpA149TyrA190 | TrpA149 (1.99) | TrpA149 TyrA195 | TrpA149 TrpB55 | |
(R)-T4 | m-O(CH2)3F | AspB173 (2.08) TyrA190 (2.66) | AspB173 | - | TrpA149TyrA190 | TyrA93 (2.18) TrpB55 (2.68, 3.12) | - | TrpA149 |
(S)-T4 | AspB173 (1.70) TrpB59 (3.39) | AspB173 | - | TrpA149 | - | TrpB55 | TrpA149 | |
(R)-T5 | m-OBn | AspB173 (1.97) TyrA190 (3.19) | AspB173 | - | TrpA149 | TyrA93 (1.94) TrpB55 (3.01, 3.09) | - | TrpA149 |
(S)-T5 | AspB173 (1.65) TrpB59 (3.08, 3.22) | AspB173 | - | TrpA149 | TyrA93 (1.85) TyrA188 (2.73, 3.37) | - | - | |
(R)-T6 | m-OCH2C6H4-p-F | AspB173 (1.95) TyrA190 (3.15) | AspB173 | - | TrpA149 TyrA190 | TyrA93 (1.90) TrpB55 (2.83, 3.02) | - | TrpA149 |
(S)-T6 | AspB173 (1.66) TrpB59 (3.00, 3.18) | AspB173 | - | TrpA149 | TyrA93 (1.96) TyrA188 (2.66, 3.32) | - | TyrA188 |
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Arunrungvichian, K.; Chongruchiroj, S.; Sarasamkan, J.; Schüürmann, G.; Brust, P.; Vajragupta, O. In Silico Finding of Key Interaction Mediated α3β4 and α7 Nicotinic Acetylcholine Receptor Ligand Selectivity of Quinuclidine-Triazole Chemotype. Int. J. Mol. Sci. 2020, 21, 6189. https://doi.org/10.3390/ijms21176189
Arunrungvichian K, Chongruchiroj S, Sarasamkan J, Schüürmann G, Brust P, Vajragupta O. In Silico Finding of Key Interaction Mediated α3β4 and α7 Nicotinic Acetylcholine Receptor Ligand Selectivity of Quinuclidine-Triazole Chemotype. International Journal of Molecular Sciences. 2020; 21(17):6189. https://doi.org/10.3390/ijms21176189
Chicago/Turabian StyleArunrungvichian, Kuntarat, Sumet Chongruchiroj, Jiradanai Sarasamkan, Gerrit Schüürmann, Peter Brust, and Opa Vajragupta. 2020. "In Silico Finding of Key Interaction Mediated α3β4 and α7 Nicotinic Acetylcholine Receptor Ligand Selectivity of Quinuclidine-Triazole Chemotype" International Journal of Molecular Sciences 21, no. 17: 6189. https://doi.org/10.3390/ijms21176189