Pyronaridine as a Bromodomain-Containing Protein 4-N-Terminal Bromodomain (BRD4-BD1) Inhibitor: In Silico Database Mining, Molecular Docking, and Molecular Dynamics Simulation
Abstract
:1. Introduction
2. Results and Discussion
2.1. Docking Protocol Validation
2.2. Virtual Screening of the SuperDRUG2 Database
2.3. Molecular Dynamics (MD)
2.4. Post-MD Analyses
2.4.1. Binding Energy Per Trajectory
2.4.2. H-Bond Analysis
2.4.3. Center-of-Mass Distance (CoM)
2.4.4. Root-Mean-Square Deviation (RMSD)
2.4.5. Root-Mean-Square Fluctuation (RMSF)
2.5. ADMET Characteristics
2.6. Drug-Likeness Characteristics
3. Computational Methods
3.1. BRD4-BD1 Preparation
3.2. Database Preparation
3.3. Docking Calculations
3.4. Molecular Dynamics (MD)
3.5. Binding Energy Evaluation
3.6. ADMET Characteristics
3.7. Drug-Likeness Characteristics
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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No. | Inhibitor Name/Code | Two-Dimensional Chemical Structure | Docking Score (kcal/mol) | Binding Features | |
---|---|---|---|---|---|
Standard | Expensive | ||||
R6S | −9.9 | −10.0 | ASN140 (H-bond, 2.71, 1.92 Å), PRO82 (H-bond, 3.04 Å; π-Alkyl, 5.07 Å), LYS91 (H- bond, 2.45 Å), ASP88 (H- bond, 1.93 Å), LEU92 (π-Alkyl, 4.75, 4.85, 5.49 Å), VAL87 (π-Alkyl, 5.22, 4.92 Å), LEU94 (π-Alkyl, 5.10 Å), PHE83 (π-Alkyl, 4.17 Å), CYS136 (π-Alkyl, 5.36 Å), ILE146 (π-Alkyl, 4.19 Å), TRP81 (π-Alkyl, 5.03 Å; π-π T-shaped, 5.25 Å) | ||
1 | Pyronaridine (SD003509) | −10.1 | −10.2 | ASN140 (H-bond, 2.32, 2.06 Å), TYR97 (H-bond, 2.67 Å), ASP88 (H-bond, 1.95 Å), PRO82 (H-bond, 2.23 Å; π-Alkyl, 5.13, 5.47 Å), LEU92 (π-Alkyl, 4.39, 4.68 Å), VAL87 (π-Alkyl, 4.44 Å), ILE146 (π-Alkyl, 4.90 Å), TRRP81 (π-π T-shaped, 4.89, 4.92 Å) | |
2 | Lumacaftor (SD003873) | −10.1 | −10.1 | GLN85 (H-bond, 2.45, 3.08 Å), LEU92 (π-Alkyl, 4.42 Å), VAL87 (π-Alkyl, 4.87 Å), ILE146 (π-Alkyl, 4.21, 4.68 Å), TRP81 (π-Alkyl, 4.87 Å; π-π T-shaped, 5.15 Å) | |
3 | N-benzoylstaurosporine (SD006001) | −9.9 | −10.0 | LEU92 (π-Alkyl, 4.50, 4.99 Å), VAL87 (π-Alkyl, 5.22, 4.86 Å), CYS136 (π-Alkyl, 5.13 Å), TRRP81 (π-π T-shaped, 5.29, 5.21 Å) |
Inhibitor Name/SuperDRUG2 Code | MM-GBSA Binding Energy (kcal/mol) | |
---|---|---|
50 ns | 200 ns | |
R6S | −43.9 | −41.5 |
Pyronaridine (SD003509) | −46.2 | −42.7 |
Lumacaftor (SD003873) | −27.8 | --- a |
N-benzoylstaurosporine (SD006001) | −20.0 | --- a |
Inhibitor Code | Absorption (A) | Distribution (D) | Metabolism (M) | Excretion (E) | Toxicity (T) | |
---|---|---|---|---|---|---|
Caco2 Permeability (cm/s) | Human Intestinal Absorption (HIA) | VDss (Human) | CYP3A4 Inhibitor/Substrate | Total Clearance | AMES Toxicity | |
Pyronaridine (SD003509) | 0.62 | 93.60 | 1.41 | Yes | 1.21 | No |
R6S | 1.12 | 90.84 | 1.15 | Yes | 0.57 | No |
Compound Name | MLogP | TPSA | nON | nOHNH | Nrotb | MWt | %ABS |
---|---|---|---|---|---|---|---|
R6S | 6.0 | 76.1 | 7 | 2 | 6 | 552.7 | 82.7 |
Pyronaridine (SD003509) | 2.8 | 90.5 | 5 | 4 | 7 | 520.1 | 77.8 |
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Ibrahim, M.A.A.; Abdelhamid, M.M.H.; Abdeljawaad, K.A.A.; Abdelrahman, A.H.M.; Mekhemer, G.A.H.; Sidhom, P.A.; Sayed, S.R.M.; Paré, P.W.; Hegazy, M.-E.F.; Shoeib, T. Pyronaridine as a Bromodomain-Containing Protein 4-N-Terminal Bromodomain (BRD4-BD1) Inhibitor: In Silico Database Mining, Molecular Docking, and Molecular Dynamics Simulation. Molecules 2023, 28, 5713. https://doi.org/10.3390/molecules28155713
Ibrahim MAA, Abdelhamid MMH, Abdeljawaad KAA, Abdelrahman AHM, Mekhemer GAH, Sidhom PA, Sayed SRM, Paré PW, Hegazy M-EF, Shoeib T. Pyronaridine as a Bromodomain-Containing Protein 4-N-Terminal Bromodomain (BRD4-BD1) Inhibitor: In Silico Database Mining, Molecular Docking, and Molecular Dynamics Simulation. Molecules. 2023; 28(15):5713. https://doi.org/10.3390/molecules28155713
Chicago/Turabian StyleIbrahim, Mahmoud A. A., Mahmoud M. H. Abdelhamid, Khlood A. A. Abdeljawaad, Alaa H. M. Abdelrahman, Gamal A. H. Mekhemer, Peter A. Sidhom, Shaban R. M. Sayed, Paul W. Paré, Mohamed-Elamir F. Hegazy, and Tamer Shoeib. 2023. "Pyronaridine as a Bromodomain-Containing Protein 4-N-Terminal Bromodomain (BRD4-BD1) Inhibitor: In Silico Database Mining, Molecular Docking, and Molecular Dynamics Simulation" Molecules 28, no. 15: 5713. https://doi.org/10.3390/molecules28155713