Molecular Basis for Non-Covalent, Non-Competitive FAAH Inhibition
Abstract
:1. Introduction
2. Results
2.1. Computational Studies
2.1.1. Identification of Putative Binding Sites of TPA14
2.1.2. Docking of TPA14 in rFAAH and mFAAH
2.1.3. Molecular Dynamics Simulations (MDs) of TPA14 in rFAAH
2.1.4. Non-Competitive Inhibition Mechanism of TPA14
2.1.5. Thermodynamic Integration (TI) Calculations
2.1.6. Molecular Dynamics Simulations (MDs) of TPA14 in mFAAH
3. Discussion and Conclusions
4. Materials and Methods
4.1. Structural Models
4.2. Molecular Docking
4.3. Molecular Dynamics Simulations (MDs)
4.4. Free-Energy Calculations
4.5. QM/MM Calculations
4.6. Thermodynamic Integration (TI)
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Ligand/Species | Box | IC50 (µM) | Pose | Cluster Size (%) | ADscore (kcal/mol) |
---|---|---|---|---|---|
TPA14/rFAAH | 1 | 0.058 | A2db1 B2db1 Ddb1 B3db1 A3db1 | 61 25 9 4 1 | −8.9 −8.7 −8.7 −8.2 −8.1 |
TPA14/rFAAH | 2 | 0.058 | A3db2 B2db2 B1db2 A1db2 A2db2 B3db2 | 55 20 3 4 2 5 | −8.7 −8.5 −8.2 −8.0 −7.9 −7.8 |
TPA14/mFAAH | 1 | 0.48 | B2db1 A2db1 A1db1 B1db1 B3db1 | 43 47 4 4 2 | −9.3 −8.9 −8.8 −8.5 −8.0 |
Pose | Cluster | Cluster Size (%) | Time (ns) | MM/GBSA | QM-MM/GBSA |
---|---|---|---|---|---|
A3db1 | a0 a1 a2 b0 b1 | 44.3 31.1 9.6 64.0 25.5 | 88–93 95–100 73–78 58–63 95–100 | −38.8(±0.4) −44.0(±0.4) n.d −41.9(±0.3) −38.2(±0.3) | n.d −52.5 n.d n.d n.d |
B3db1 | a0 b0 | 99.7 100 | 80.5–85.5 95–100 | −43.7(±0.4) −49.3(±0.4) | n.d −66.0 |
TPA1 Pose | QM-MM/GBSA |
---|---|
A1 | −71.62 |
B3 | −61.28 |
TPA14 Pose | Cluster | Cluster Size (%) | Time (ns) | MM/GBSA | QM-MM/GBSA |
---|---|---|---|---|---|
A2db1 | a0 b0 b1 | 92.4 58.3 40.3 | 95–100 95–100 38–43 | −42.54 (±0.31) −45.77 (±0.34) −41.08 (±0.35) | n.d. −59.58 n.d |
B2db1 | a0 b1 b0 b1 b2 | 64.7 21.8 47.5 41.6 10.6 | 95–100 27–32 95–100 48–53 5–10 | −46.34 (±0.35) −43.98 (±0.39) −42.34 (±0.36) −43.79 (±0.35) −42.3 (±0.31) | −51.97 n.d n.d n.d n.d |
A3db1 | a0 a1 b0 b1 b2 | 81.3 11 39.5 27.3 21.3 | 95–100 29–34 92–95 21–26 47–52 | −47.82 (±0.37) −44.26 (0.4) −41.73 (0.32) −39.54 (0.39) −37.83 (0.32) | −45.84 n.d n.d n.d n.d |
B3db1 | a0 b0 b1 | 95.5 62 18.5 | 95–100 95–100 18–23 | −48.27 (0.35) −39.01 (0.37) −37.32 (0.28) | −46.98 n.d n.d |
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Morgillo, C.M.; Lupia, A.; Deplano, A.; Pirone, L.; Fiorillo, B.; Pedone, E.; Luque, F.J.; Onnis, V.; Moraca, F.; Catalanotti, B. Molecular Basis for Non-Covalent, Non-Competitive FAAH Inhibition. Int. J. Mol. Sci. 2022, 23, 15502. https://doi.org/10.3390/ijms232415502
Morgillo CM, Lupia A, Deplano A, Pirone L, Fiorillo B, Pedone E, Luque FJ, Onnis V, Moraca F, Catalanotti B. Molecular Basis for Non-Covalent, Non-Competitive FAAH Inhibition. International Journal of Molecular Sciences. 2022; 23(24):15502. https://doi.org/10.3390/ijms232415502
Chicago/Turabian StyleMorgillo, Carmine Marco, Antonio Lupia, Alessandro Deplano, Luciano Pirone, Bianca Fiorillo, Emilia Pedone, F. Javier Luque, Valentina Onnis, Federica Moraca, and Bruno Catalanotti. 2022. "Molecular Basis for Non-Covalent, Non-Competitive FAAH Inhibition" International Journal of Molecular Sciences 23, no. 24: 15502. https://doi.org/10.3390/ijms232415502