Human Target Proteins for Benzo(a)pyrene and Acetaminophen (And Its Metabolites): Insights from Inverse Molecular Docking and Molecular Dynamics Simulations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Virtual Screening for Selection of Human Proteins
2.2. Molecular Docking with AutoDock Vina
2.2.1. Compounds’ Structures
2.2.2. Preparation of Protein Structures
2.2.3. Docking Calculations
2.3. Protein–Ligand Interaction Prediction
2.4. Validation of Docking Protocol
2.5. Molecular Dynamics Simulations (MDS)
3. Results
3.1. Virtual Screening by Automatic Docking Generation
3.2. Docking Analysis
3.3. The Nature of the Interactions of Protein–Ligand Complexes
3.4. Docking Validation
3.5. Molecular Dynamics Simulations
3.5.1. Root Mean Square Deviations (RSMD)
3.5.2. Root Mean Square Fluctuation (RMSF)
3.5.3. Hydrogen Bond Analysis
3.5.4. Molecular Mechanics Energies Combined with Surface Area Continuum Solvation (MMGBSA)
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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GO-Term | Biological Process | Count in Network | Strength | False Discovery Rate |
---|---|---|---|---|
GO:1905323 | Telomerase holoenzyme complex assembly | 2 of 4 | 2.43 | 0.0036 |
GO:1902949 | Positive regulation of tau protein kinase activity | 2 of 7 | 2.18 | 0.0073 |
GO:0048384 | Retinoic acid receptor signaling pathway | 4 of 18 | 2.07 | 2.39 × 10−5 |
GO:2000074 | Regulation of type B pancreatic cell development | 2 of 9 | 2.07 | 0.0100 |
GO:0045725 | Positive regulation of glycogen biosynthetic process | 3 of 15 | 2.03 | 0.00058 |
GO:0070989 | Oxidative demethylation | 3 of 19 | 1.92 | 0.00097 |
GO:0090201 | Negative regulation of release of cytochrome c from mitochondria | 2 of 21 | 1.71 | 0.0333 |
GO:0010875 | Positive regulation of cholesterol efflux | 2 of 26 | 1.61 | 0.0444 |
GO:0006633 | Fatty acid biosynthetic process | 5 of 119 | 1.35 | 0.00043 |
GO:0032436 | Positive regulation of proteasomal ubiquitin-dependent protein catabolic process | 4 of 96 | 1.35 | 0.0029 |
GO:2001237GO:2001237 | Negative regulation of extrinsic apoptotic signaling pathway | 4 of 97 | 1.34 | 0.0030 |
GO:2000573 | Positive regulation of DNA biosynthetic process | 3 of 73 | 1.34 | 0.0181 |
GO:0033674 | Positive regulation of kinase activity | 6 of 494 | 0.81 | 0.0150 |
GO:0010629 | Negative regulation of gene expression | 10 of 899 | 0.77 | 0.00056 |
GO:0010628 | Positive regulation of gene expression | 11 of 1146 | 0.71 | 0.00065 |
Average Affinity Values (kcal/mol) | ||||||
---|---|---|---|---|---|---|
PDB ID | Description | B[a]P | APAP | AM404 | NAPQI | APAP- GLUCURONIDE |
1P8D | Oxysterol receptor LXR-beta | −12.7 ± 0 | −6.3 ± 0.1 | −9.0 ± 0.2 | −6.7 ± 0.1 | −9.0 ± 0.1 |
3NMQ | Heat shock protein HSP 90-beta | −11.7 ± 0 | −6.4 ± 0.2 | −8.3 ± 0.1 | −6.6 ± 0.1 | −7.4 ± 0.2 |
3O96 | RAC-alpha serine/ threonine protein kinase | −12.5 ± 0 | −6.4 ± 0 | −9.1 ± 0.1 | −6.7 ± 0 | −8.2 ± 0 |
4ACG | Glycogen synthase kinase-3 beta | −10.6 ± 0.2 | −5.6 ± 0 | −7.0 ± 0.1 | −5.6 ± 0 | −6.7 ± 0 |
5J20 | Heat shock protein HSP 90-alpha | −11.0 ± 0 | −6.5 ± 0 | −8.1 ± 0.6 | −6.7 ± 0.1 | −7.6 ± 0.3 |
Protein | Ligand | Total Binding Free Energy (kcal/mol) | van der Waals Energy (kcal/mol) | Electrostatic Energy (kcal/mol) | Polar Solvation Energy (kcal/mol) | SASA Energy (kcal/mol) | Delta G Gas | Delta G Solv |
---|---|---|---|---|---|---|---|---|
1P8D | CO1 | −48.55 ± 0.32 | −59.61 ± 0.26 | −7.48 ± 0.51 | 25.4 ± 0.50 | −6.85 ± 0.02 | −67.09 ± 0.60 | 18.55 ± 0.50 |
AM404 | −37.95 ± 0.66 | −51.93 ± 0.47 | −13.9 ± 0.63 | 35.58 ± 0.59 | −7.69 ± 0.04 | −65.84 ± 0.82 | 27.89 ± 0.58 | |
BP | −19.79 ± 0.31 | −32.45 ± 0.32 | −2.09 ± 0.25 | 18.77 ± 0.37 | −4.02 ± 0.03 | −34.53 ± 0.42 | 14.74 ± 0.36 | |
3NMQ | 7PP | −17.08 ± 0.48 | −49.4 ± 0.38 | −19.73 ± 1.25 | 58.22 ± 1.23 | −6.16 ± 0.03 | −69.14 ± 1.29 | 52.05 ± 1.21 |
AM404 | −40.52 ± 0.77 | −54.12 ± 0.67 | −9.423 ± 0.46 | 30.72 ± 0.40 | −7.69 ± 0.07 | −63.55 ± 0.86 | 23.03 ± 0.38 | |
B(a)P | −20.41 ± 0.32 | −34.14 ± 0.39 | −2.81 ± 0.26 | 20.38 ± 0.30 | −3.84 ± 0.03 | −36.95 ± 0.44 | 16.54 ± 0.29 | |
3O96 | 1QO | −37.97 ± 0.39 | −73.43 ± 0.33 | −26.8 ± 0.82 | 70.37 ± 0.75 | −8.11 ± 0.02 | −100.23 ± 0.83 | 62.3 ± 0.73 |
AM404 | −38.28 ± 0.59 | −52.8 ± 0.44 | −27.22 ± 0.74 | 42.72 ± 0.48 | −7.99 ± 0.05 | −80.02 ± 0.66 | 41.73 ± 0.48 | |
B(a)P | −20.46 ± 0.20 | −35.48 ± 0.24 | −2.29 ± 0.19 | 21.24 ± 0.22 | −3.93 ± 0.02 | −37.77 ± 0.30 | 17.3 ± 0.22 | |
4ACG | 6LQ | −41.67 ± 0.88 | −53.29 ± 0.51 | −31.99 ± 0.95 | 50.49 ± 0.57 | −6.88 ± 0.04 | −85.28 ± 0.92 | 43.61 ± 0.57 |
AM404 | −35.32 ± 0.86 | −44.99 ± 0.54 | −14.11 ± 1.59 | 30.44 ± 0.96 | −6.65 ± 0.06 | −59.1 ± 1.66 | 23.79 ± 0.95 | |
B(a)P | −20.46 ± 0.32 | −30.65 ± 0.38 | −4.31 ± 0.29 | 18.27 ± 0.22 | −3.77 ± 0.04 | −34.97 ± 0.42 | 14.5 ± 0.20 | |
5J20 | 6FJ | −27.11 ± 0.43 | −44.18 ± 0.38 | −37.73 ± 0.82 | 60.48 ± 0.68 | −5.68 ± 0.03 | −81.91 ± 0.80 | 54.8 ± 0.66 |
AM404 | −40.66 ± 0.62 | −56.72 ± 0.50 | −15.3 ± 0.68 | 39.51 ± 0.51 | −8.15 ± 0.04 | −72.02 ± 0.87 | 31.36 ± 0.50 | |
B(a)P | −22.89 ± 0.21 | −36.09 ± 0.20 | −3.49 ± 0.24 | 20.6 ± 0.26 | −3.92 ± 0.017 | −39.59 ± 0.27 | 16.69 ± 0.25 |
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Montero-Pérez, Y.; Pájaro-Castro, N.; Coronado-Posada, N.; Ahumedo-Monterrosa, M.; Olivero-Verbel, J. Human Target Proteins for Benzo(a)pyrene and Acetaminophen (And Its Metabolites): Insights from Inverse Molecular Docking and Molecular Dynamics Simulations. Sci. Pharm. 2024, 92, 55. https://doi.org/10.3390/scipharm92040055
Montero-Pérez Y, Pájaro-Castro N, Coronado-Posada N, Ahumedo-Monterrosa M, Olivero-Verbel J. Human Target Proteins for Benzo(a)pyrene and Acetaminophen (And Its Metabolites): Insights from Inverse Molecular Docking and Molecular Dynamics Simulations. Scientia Pharmaceutica. 2024; 92(4):55. https://doi.org/10.3390/scipharm92040055
Chicago/Turabian StyleMontero-Pérez, Yina, Nerlis Pájaro-Castro, Nadia Coronado-Posada, Maicol Ahumedo-Monterrosa, and Jesus Olivero-Verbel. 2024. "Human Target Proteins for Benzo(a)pyrene and Acetaminophen (And Its Metabolites): Insights from Inverse Molecular Docking and Molecular Dynamics Simulations" Scientia Pharmaceutica 92, no. 4: 55. https://doi.org/10.3390/scipharm92040055