In Silico Core Proteomics and Molecular Docking Approaches for the Identification of Novel Inhibitors against Streptococcus pyogenes
Abstract
:1. Introduction
2. Materials and Methods
2.1. Core Proteome Retrieval
2.2. Identification of Drug Targets
2.3. Structure Prediction
2.4. Structure Evaluation
2.5. Preparation of Target Proteins
2.6. Library Preparation
2.7. Molecular Docking Analysis
2.8. Evaluation of Inhibitors’ Druglikeness
2.9. ADMET Profiling
2.10. Molecular Dynamics Simulation Protocol
2.11. MMPB/GBSA Analysis
3. Results
3.1. Core Proteome Retrieval
3.2. Identification of Drug Targets
3.3. Structure Prediction
3.4. Model Evaluation
3.5. Molecular Docking Analysis
3.6. Druglikeness Prediction
3.7. ADMET Profiling
3.8. MD Simulation
3.9. Binding Free Energy Calculations
4. Discussion
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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Name | Common Pathways | Unique Pathways |
---|---|---|
Glucose-6-phosphate isomerase | Metabolic pathways Glycolysis Carbon metabolism Pentose phosphate pathway Amino sugar and nucleotide sugar metabolism Starch and sucrose metabolism | Biosynthesis of secondary metabolites Microbial metabolism in diverse environments |
UDP-N-acetylenolpyruvoylglucosamine reductase | Metabolic pathways Amino sugar and nucleotide sugar metabolism | Peptidoglycan biosynthesis |
Riboflavin biosynthesis protein | Biosynthesis of cofactors Metabolic pathways Riboflavin metabolism | Biosynthesis of secondary metabolites |
Alanine racemase | Metabolic pathways | d-Alanine metabolism Vancomycin resistance |
Chromosomal replication initiator protein DnaA | Two-component system | |
Two-component response regulator | Two-component system | |
Phosphate acyltransferase | Glycerolipid metabolism Metabolic pathways | Biosynthesis of secondary metabolites |
Fructose-bisphosphate aldolase | Metabolic pathways Glycolysis Carbon metabolism Biosynthesis of amino acids Fructose and mannose metabolism Pentose phosphate pathway Methane metabolism | Biosynthesis of secondary metabolites Microbial metabolism in diverse environments |
UDP-N-acetylmuramoyl-tripeptide—D-alanyl- D-alanine ligase | Metabolic pathways | Vancomycin resistance Peptidoglycan biosynthesis |
Acetyl-coenzyme A carboxylase carboxyl transferase subunit alpha | Metabolic pathways | Biosynthesis of secondary metabolites |
Target Proteins | Ramachandran Plot Statistics (%) | Verify 3D | ERRAT | ProSA | |||
---|---|---|---|---|---|---|---|
Core | Allowed | General | Disallowed | Compatibility Score (%) | Quality Factor | z-Score | |
Chromosomal replication initiator protein DnaA | 88.4% | 10.0% | 1.6% | 0.0% | 74.71% | 90.0602 | −8.48 |
Two-component response regulator | 89.6% | 9.5% | 0.5% | 0.5% | 85.47% | 92.4779 | −7.86 |
Target Proteins | Compound ID’s | Compounds Name | Docking Score (kcal/mol) | RMSD | Interacting Residues |
---|---|---|---|---|---|
DNaA Protein | 11216065 | Sophorastilbene A | −21.31 | 3.61 | Phe121 Lys115 Lys291 Asn290 |
72427 | Daphnodorin B | −20.77 | 1.70 | Lys115 Lys291 | |
443652 | Oenin | −20.18 | 1.96 | Lys115 | |
12096478 | Flavumone A | −20.06 | 2.32 | Lys115 Lys291 | |
72426 | Daphnodorin A | −16.00 | 3.26 | Lys115 Lys291 | |
TCR protein | 14989 | Aloin B | −18.02 | 1.55 | Arg118 His72 |
1794427 | Chlorogenic acid | −17.47 | 1.23 | Lys2 Arg118 Phe150 Leu161 | |
71597391 | Triterpenoids | −17.47 | 1.42 | Lys2 Arg118 | |
5380394 | Veratrine | −16.96 | 2.22 | Arg118 Phe150 | |
118855584 | 1,6-Dihydroxy-3-methyl-8-[(2S,5S)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyanthracene-9,10-dione | −16.84 | 1.51 | Asp47 Lys2 |
Target Proteins | Compounds | Molecular Weight (g/mol) | Number of HBA (nON) | Number of HBD (nOHNH) | mi-LogP |
---|---|---|---|---|---|
DNaA | 11216065 | 673.65 | 9 | 3 | 4.36 |
72427 | 539.47 | 10 | 4 | 2.24 | |
443652 | 491.43 | 12 | 5 | −2.39 | |
12096478 | 538.46 | 10 | 5 | 2.29 | |
72426 | 524.48 | 9 | 4 | 3.25 | |
TCR | 14989 | 416.38 | 9 | 5 | −3.04 |
1794427 | 352.30 | 9 | 4 | −3.24 | |
71597391 | 470.65 | 5 | 2 | 1.70 | |
5380394 | 590.73 | 10 | 5 | −0.54 | |
118855584 | 430.37 | 10 | 4 | −1.82 |
Standard Parameters | Target | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
DNaA | TCR | |||||||||
11216065 | 72427 | 443652 | 12096478 | 72426 | 14989 | 1794427 | 71597391 | 5380394 | 118855584 | |
Absorption | ||||||||||
Aqueous solubility (LogS) | −3.3170 | −3.2562 | −2.7564 | −3.0485 | −2.9143 | −2.3269 | −2.5951 | −3.9108 | −2.4829 | −2.8081 |
Human Intestinal Absorption | 0.9727 | + 0.9394 | −0.9165 | +0.9300 | +0.8623 | +0.7201 | −0.8658 | +0.7320 | −0.7652 | −0.8845 |
Blood Brain Barrier | +0.8635 | +0.7154 | −0.8897 | +0.6248 | +0.7183 | +0.5432 | +0.5612 | +0.7302 | −0.8131 | −0.6852 |
Caco-2 permeability | −0.6888 | −0.8292 | −0.4982 | −0.0172 | 0.6303 | 0.2248 | −0.5040 | 1.1647 | 0.2244 | −0.4438 |
Distribution | ||||||||||
P-gp Substrate | Non-Substrate | Non-Substrate | Substrate | Substrate | Substrate | Substrate | Substrate | Substrate | Substrate | Substrate |
P-gp Inhibitor | Non-Inhibitor | Non-Inhibitor | Non-Inhibitor | Non-Inhibitor | Non-Inhibitor | Non-Inhibitor | Non-Inhibitor | Non-Inhibitor | Inhibitor | Non-Inhibitor |
Metabolism | ||||||||||
CYP450 2D6 Substrate | x | x | x | X | x | x | x | x | x | x |
CYP450 3A4 Substrate | x | x | √ | X | x | x | x | √ | √ | x |
CYP450 1A2 Inhibitor | √ | √ | X | √ | √ | x | x | x | x | x |
CYP450 2C9 Inhibitor | √ | √ | X | √ | √ | x | x | x | x | x |
CYP450 2D6 Inhibitor | x | x | X | X | x | x | x | x | x | x |
CYP450 2C19 Inhibitor | √ | √ | X | X | √ | x | x | x | x | x |
CYP450 3A4 Inhibitor | x | √ | X | X | √ | x | x | x | x | x |
Toxicity | ||||||||||
Salmonella typhimurium reverse mutation assay AMES Test | Non-AMES Toxic | Non-AMES Toxic | Non-AMES Toxic | Non-AMES Toxic | Non-AMES Toxic | AMES Toxic | Non-AMES Toxic | Non-AMES Toxic | Non-AMES Toxic | AMES Toxic |
Human Ether-à-go-go-Related Gene (hERG) Inhibition | Weak inhibitors | Weak inhibitors | Weak inhibitors | Weak inhibitors | Weak inhibitors | Weak inhibitor | Weak inhibitor | Weak inhibitor | Weak inhibitor | Weak inhibitor |
Carcinogens | Non-Carcinogens | Non-Carcinogens | Non-Carcinogens | Non-Carcinogens | Non-Carcinogens | Non-Carcinogens | Non-Carcinogens | Non-Carcinogens | Non-Carcinogens | Non-Carcinogens |
Rat Acute Toxicity (LD50, mol/kg) | 2.4083 | 2.5846 | −2.7564 | 2.5248 | 3.0847 | 2.5732 | 2.6020 | 2.8611 | 3.3693 | 2.9432 |
Energy Parameter | TCR | DNaA | ||
---|---|---|---|---|
14989-Complex | 1794427-Complex | 72427-Complex | 11216065-Complex | |
MM-GBSA | ||||
VDWAALS | −22.23 | −21.65 | −18.16 | −22.46 |
EEL | −10.11 | −9.10 | −11.21 | −10.58 |
EGB | 13.20 | 12.11 | 16.58 | 15.21 |
ESURF | −2.00 | −2.54 | −3.39 | −4.00 |
Delta G gas | −32.34 | −30.75 | −29.37 | −33.04 |
Delta G solv | 11.20 | 9.57 | 13.13 | 11.21 |
Delta Total | −21.14 | −21.18 | −16.24 | −21.83 |
MM-PBSA | ||||
VDWAALS | −22.23 | −21.65 | −18.16 | −22.46 |
EEL | −10.11 | −9.10 | −11.21 | −10.58 |
EPB | 10.28 | 6.28 | 12.07 | 9.41 |
ENPOLAR | −5.00 | −3.96 | −2.98 | −3.51 |
Delta G gas | −32.34 | −30.75 | −29.37 | −33.04 |
Delta G solv | 5.28 | 2.32 | 9.09 | 5.9 |
Delta Total | −27.06 | −28.43 | −20.28 | −27.14 |
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Rehman, A.; Wang, X.; Ahmad, S.; Shahid, F.; Aslam, S.; Ashfaq, U.A.; Alrumaihi, F.; Qasim, M.; Hashem, A.; Al-Hazzani, A.A.; et al. In Silico Core Proteomics and Molecular Docking Approaches for the Identification of Novel Inhibitors against Streptococcus pyogenes. Int. J. Environ. Res. Public Health 2021, 18, 11355. https://doi.org/10.3390/ijerph182111355
Rehman A, Wang X, Ahmad S, Shahid F, Aslam S, Ashfaq UA, Alrumaihi F, Qasim M, Hashem A, Al-Hazzani AA, et al. In Silico Core Proteomics and Molecular Docking Approaches for the Identification of Novel Inhibitors against Streptococcus pyogenes. International Journal of Environmental Research and Public Health. 2021; 18(21):11355. https://doi.org/10.3390/ijerph182111355
Chicago/Turabian StyleRehman, Abdur, Xiukang Wang, Sajjad Ahmad, Farah Shahid, Sidra Aslam, Usman Ali Ashfaq, Faris Alrumaihi, Muhammad Qasim, Abeer Hashem, Amal A. Al-Hazzani, and et al. 2021. "In Silico Core Proteomics and Molecular Docking Approaches for the Identification of Novel Inhibitors against Streptococcus pyogenes" International Journal of Environmental Research and Public Health 18, no. 21: 11355. https://doi.org/10.3390/ijerph182111355
APA StyleRehman, A., Wang, X., Ahmad, S., Shahid, F., Aslam, S., Ashfaq, U. A., Alrumaihi, F., Qasim, M., Hashem, A., Al-Hazzani, A. A., & Abd_Allah, E. F. (2021). In Silico Core Proteomics and Molecular Docking Approaches for the Identification of Novel Inhibitors against Streptococcus pyogenes. International Journal of Environmental Research and Public Health, 18(21), 11355. https://doi.org/10.3390/ijerph182111355