Hepatitis C Virus NS3/4A Inhibition and Host Immunomodulation by Tannins from Terminalia chebula: A Structural Perspective
Abstract
:1. Introduction
2. Materials and Methods
2.1. Retrieval of Phytocompounds
2.2. Target Identification
2.3. Gene Set Enrichment Analysis
2.4. Network Construction
2.5. Molecular Docking Studies
2.5.1. Preparation of Ligand and Protein
2.5.2. Assessment of Active Site Residues
2.5.3. Protein–Ligand Docking
2.6. Molecular Dynamics (MD) Simulation
2.7. Druglikeness, Side Effects, and Toxicity of Phytocompounds
3. Results
3.1. Retrieval of Phytocompounds and Target Identification
3.2. Gene Set Enrichment Analysis and Network Analysis
3.3. Protein Quality Check and Stability Analysis by Molecular Dynamics Simulation
3.4. Assessment of Active Site Residues
3.5. Ligand–Protein Docking
3.6. Molecular Dynamics Simulation of NS3/4A–Ligand Complexes
3.6.1. Asunaprevir–NS3/4A Complex
3.6.2. Chebulagic Acid–NS3/4A Complex
3.6.3. 1,2,3,4,6-Pentagalloyl Glucose–NS3/4A Complex
3.7. Druglikeness, Side Effects, and Toxicity of Phytocompounds
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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Phytocompounds | PubChem ID | Structural Similarity (p ≥ 0.7–1) | Experimental Assay | Reference Compound PubChem CID | Experimental IC50 of Reference Compound (µM) | References |
---|---|---|---|---|---|---|
1,2,3,4,6-Pentagalloyl glucose | 374874 | 1 | Inhibitory activity against HCV NS3 protease by ELISA | 15945060 | 0.75 | [46] |
1,3,4,6-Tetra-O-galloyl-β-D-glucose | 471531 | 0.98 | ||||
1,3,6-Tri-O-galloyl-β-D-glucose | 452707 | 0.98 | ||||
1,6,-di-O-galloyl-D-glucose | 91227631 | 0.94 | ||||
2,3,4,6 tetra-O-galloyl-β-D-glucose | 101011018 | 0.7 | ||||
3,4,6-tri-O-galloyl-D-glucose | 14188641 | 0.87 | ||||
Chebulagic acid | 250397 | 0.7 | HCV NS3 protease binding assay | 511658 | 0.3 | [59] |
511659 | 0.8 | [59] | ||||
Corilagin | 73568 | 0.74 | HCV NS3 protease binding assay | 511658 | 0.3 | [59] |
511659 | 0.8 | [59] | ||||
Inhibitory activity against HCV NS3 protease by ELISA | 15945060 | 0.75 | [46] | |||
Tellimagrandin I | 442690 | 0.7 | HCV NS3 protease binding assay | 511658 | 0.3 | [59] |
511659 | 0.8 | [59] | ||||
Inhibitory activity against HCV NS3 protease by ELISA | 15945060 | 0.75 | [46] | |||
Tercatain | 14411426 | 0.75 | HCV NS3 protease binding assay | 511658 | 0.3 | [59] |
511659 | 0.8 | [59] | ||||
Inhibitory activity against HCV NS3 protease by ELISA | 15945060 | 0.75 | [46] |
Reactome ID | Pathways | Gene Count | Background Gene Count | FDR | Genes within Pathway |
---|---|---|---|---|---|
HSA-109582 | Hemostasis | 8 | 601 | 1.52E-05 | F10, F11, F2, LCK, PLAT, PLAU, PTPN1, SERPINE1 |
HSA-140837 | Intrinsic pathway of fibrin clot formation | 3 | 22 | 0.00014 | F10, F11, F2 |
HSA-140877 | Formation of fibrin clot (clotting cascade) | 3 | 39 | 0.00051 | F10, F11, F2 |
HSA-162582 | Signal transduction | 11 | 2605 | 0.00051 | F2, HSP90AA1, LCK, PDK1, PLAT, PTPN1, PTPN2, RGS4, RGS7, RGS8, SERPINE1 |
HSA-9006934 | Signaling by receptor tyrosine kinases | 5 | 437 | 0.0019 | HSP90AA1, LCK, PLAT, PTPN1, PTPN2 |
HSA-76002 | Platelet activation, signaling, and aggregation | 4 | 256 | 0.0023 | F2, LCK, PTPN1, SERPINE1 |
HSA-6807004 | Negative regulation of MET activity | 2 | 20 | 0.0038 | PTPN1, PTPN2 |
HSA-140875 | Common pathway of fibrin clot formation | 2 | 22 | 0.0042 | F10, F2 |
HSA-1280215 | Cytokine signaling in immune system | 5 | 654 | 0.0062 | GSTO1, HSP90AA1, LCK, PTPN1, PTPN2 |
HSA-76009 | Platelet aggregation (plug formation) | 2 | 37 | 0.0096 | F2, PTPN1 |
HSA-449147 | Signaling by interleukins | 4 | 439 | 0.0111 | GSTO1, HSP90AA1, LCK, PTPN2 |
HSA-168256 | Immune system | 7 | 1925 | 0.0245 | F2, GSTO1, HSP90AA1, LCK, PLAU, PTPN1, PTPN2 |
Phytocompounds | PubChem CID | BE (kcal/mol) | Total No. of Interactions | No. of Interactions with Active Site Residues | HBI (Amino Acid…Ligand) | Van der Waals, Pi–Alkyl, CH, Pi–Cation, Pi–Sigma, Pi–Pi Stacked, Pi–Pi T-Shaped Interactions |
---|---|---|---|---|---|---|
1,2,3,4,6-Pentagalloyl glucose | 374874 | −7.7 | 20 | 20 | Gln1041…OH, His1057…OH (2), Asp1081…OH, Ile1132…OH, Ser1139…O-, Ser1139…OH (2), Arg1155…O- (2) | Val1055, His1057 (2), Gly1058, Ile1132, Lys1136, Ala1156 (3), Ala1157 |
1,3,4,6-Tetra-O-galloyl-β-D-glucose | 471531 | −7.6 | 14 | 14 | Gln1041…OH, Asp1081…OH, Ile1132…OH, Ser1139…OH (2), Ser1139…O- (2), Arg1155…OH | Ile1132, Lys1136 (2), Gly1137, Ala1156, Ala1157 |
1,3,6-Tri-O-galloyl-β-D-glucose | 452707 | −7.0 | 8 | 8 | Gly1058…O-, Gly1137…O-, Ser1139….O- (2), Ser1139…OH | His1057, Lys1136, Ala1156 |
1,6,-di-O-galloyl-D-glucose | 91227631 | −6.6 | 6 | 5 | Thr1042…OH, Ile1132…OH, Ser1139…O- | His1057 (2), Lys1136 |
2,3,4,6 tetra-O-galloyl-β-D-glucose | 101011018 | −6.5 | 11 | 11 | Gln1041…OH, Ser1139…OH (3) | Ile1132, Lys1136, Gly1137, Ser1139, Ala1156 (2), Ala1157 |
3,4,6-tri-O-galloyl-D-glucose | 14188641 | −6.6 | 11 | 10 | Gln1041…OH, Thr1042…OH, Ile1132…OH, Ser1139…OH, Ser1139…O- | His1057, Ile1132, Lys1136, Gly1137, Ala1156, Ala1157 |
Chebulagic acid | 250397 | −8.4 | 13 | 11 | Gly1137…O-, Arg1155…=O, Arg1155…=O, Gly1058…O-, Ile1132…OH (2), Ser1159…OH (2) | Lys1136 (2), His1057, Ile1132, Ser1139 |
Corilagin | 73568 | −7.3 | 3 | 3 | Gln1041…OH, His1057…O- | Lys1136 |
Tellimagrandin I | 442690 | −7.7 | 10 | 9 | Gln1041…OH, Thr1042…OH, Gly1058…O-, Ser1139…=O, Ala1157…O- | His1057, Ile1132 (2), Lys1136, Ala1157 |
Tercatain | 14411426 | −7.5 | 8 | 6 | Leu1135…OH, Ser1139…O-, Ser1159…OH, Ser1159…O- | His1057 (2), Lys1136, Ala1156 |
* Asunaprevir | 16076883 | −7.4 | 20 | 20 | Gly1137…=O (2), Ala1157…NH, Ala1157…=O | Arg1155 (2), Asp1081 (2), His1057 (2), Ala1156 (4), Ile1132 (3), Val1158 (2), Lys1136 (2) |
Compound/Ligand Name | Amino Acid Residue | Ligand Atom | Ligand Atom Position | Ligand Atom Interactions with the Protein Residues (%) |
---|---|---|---|---|
Asunaprevir | Gly1137 | =O | 16 | 97 |
Ala1157 | =O | 7 | 99 | |
Ala1157 | NH | 44 | 82 | |
Ser1139 | =O | 9 | 56 | |
Ser1159 | -O | 47 | 46 | |
Gln1041 | +O | 18 | 39 | |
Thr1042 | -O | 18 | 38 | |
Thr1042 | -O | 18 | 28 | |
Chebulagic acid | Ala1157 | =O | 41 | 61 |
Asp1081 | OH | 68 | 51 | |
Asp1081 | =O | 67 | 38 | |
Asp1168 | =O | 20 | 31 | |
Ile1132 | OH | 46 | 45 | |
Arg1155 | OH | 50 | 31 | |
His1057 | π-π | 25–30 | 46 | |
1,2,3,4,6-Pentagalloyl glucose | Asp1081 | OH | 41 | 99 |
Asp1081 | OH | 40 | 99 | |
Arg1155 | OH | 42 | 37 | |
Arg1155 | OH | 42 | 22 | |
Gly1137 | OH | 65 | 41 | |
Ser1139 | OH | 65 | 61 | |
Ser1139 | OH | 66 | 72 | |
Leu1135 | OH | 67 | 47 | |
Leu1157 | OH | 67 | 32 | |
Tyr1056 | OH | 18 | 23 | |
His1057 | OH | 18 | 23 |
Phytocompounds | MW (g/mol) | MF | HBA | HBD | LogP | DLS |
---|---|---|---|---|---|---|
1,2,3,4,6-Pentagalloyl glucose | 940.12 | C41 H32 O26 | 26 | 15 | 1.47 | 0.19 |
1,3,4,6-Tetra-O-galloyl-β-D-glucose | 788.11 | C34 H28 O22 | 22 | 13 | 0.62 | 0.92 |
1,3,6-Tri-O-galloyl-β-D-glucose | 636.1 | C27 H24 O18 | 18 | 11 | −0.08 | 0.92 |
1,6,-di-O-galloyl-D-glucose | 484.09 | C20 H20 O14 | 14 | 9 | 0.8 | 0.9 |
2,3,4,6 tetra-O-galloyl-β-D-glucose | 788.11 | C34 H28 O22 | 22 | 13 | 0.1 | 0.44 |
3,4,6-tri-O-galloyl-D-glucose | 636.1 | C27 H24 O18 | 18 | 11 | −0.2 | 0.87 |
Chebulagic acid | 954.1 | C41 H30 O27 | 27 | 13 | 0.22 | 0.58 |
Corilagin | 634.08 | C27 H22 O18 | 18 | 11 | 0.51 | 0.64 |
Tellimagrandin I | 786.09 | C34 H26 O22 | 22 | 13 | 1.15 | 0.3 |
Tercatain | 786.09 | C34 H26 O22 | 22 | 13 | 1.21 | 0.65 |
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Patil, V.S.; Harish, D.R.; Vetrivel, U.; Roy, S.; Deshpande, S.H.; Hegde, H.V. Hepatitis C Virus NS3/4A Inhibition and Host Immunomodulation by Tannins from Terminalia chebula: A Structural Perspective. Molecules 2022, 27, 1076. https://doi.org/10.3390/molecules27031076
Patil VS, Harish DR, Vetrivel U, Roy S, Deshpande SH, Hegde HV. Hepatitis C Virus NS3/4A Inhibition and Host Immunomodulation by Tannins from Terminalia chebula: A Structural Perspective. Molecules. 2022; 27(3):1076. https://doi.org/10.3390/molecules27031076
Chicago/Turabian StylePatil, Vishal S., Darasaguppe R. Harish, Umashankar Vetrivel, Subarna Roy, Sanjay H. Deshpande, and Harsha V. Hegde. 2022. "Hepatitis C Virus NS3/4A Inhibition and Host Immunomodulation by Tannins from Terminalia chebula: A Structural Perspective" Molecules 27, no. 3: 1076. https://doi.org/10.3390/molecules27031076