An In Vivo and In Silico Approach Reveals Possible Sodium Channel Nav1.2 Inhibitors from Ficus religiosa as a Novel Treatment for Epilepsy
Abstract
1. Introduction
2. Materials and Methods
2.1. Collection of Plant Material, Extract Preparation, and Fractionation
2.2. Experimental Animal Studies
2.2.1. In Vivo Study Design
2.2.2. Maximal Electroshock (MES)-Induced Seizure Test
2.2.3. Statistical Analysis
2.3. In Silico Studies
2.3.1. Preparation of Protein
2.3.2. Ligand Selection and Preparation
2.3.3. Molecular Docking
2.3.4. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) Simulation
2.3.5. Molecular Dynamics (MD) Simulation
2.3.6. Absorption, Distribution, Metabolism, Elimination (ADME) Analysis
2.3.7. Toxicity Prediction Study
3. Results
3.1. Maximal Electroshock (MES)-Induced Seizure Model
3.2. Molecular Docking
3.3. MM/GBSA Studies
3.4. Molecular Dynamics Simulation
3.5. Drug-likeness Predictions
3.6. Toxicity Predictions
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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Group | Treatment Groups | Pre-Treatment | No. of Animals | Onset Time for THLE (sec) |
---|---|---|---|---|
1 | Control | Normal Saline | 6 | 11.00 ± 2.97 |
2 | Standard | Phenytoin | 6 | 1.17 ± 1.33 ** |
3 | PE-Fr | PE-Fr | 6 | 2.67 ± 1.96 * |
4 | EA-Fr | EA-Fr | 6 | 3.00 ± 1.26 * |
Prime MM/GBSA | |||||||
---|---|---|---|---|---|---|---|
Ligand | Name | Molecular Formula | Molecular Weight (g/mol) | Docking Score | XPGScore | Glide Score | ΔGbind |
g/mol | kcal/mol | kcal/mol | kcal/mol | kcal/mol | |||
1 | Luteolin 7-O-rutinoside | C27H30O15 | 610.5 | −13.476 | −13.476 | −13.476 | −62.13 |
2 | Pelargonidin-3- rhamnoside | C21H21O9+ | 417.4 | −8.894 | −10.301 | −10.301 | −45.82 |
3 | 6-C-glucosyl-8-C- arabinosyl apigenin | C26H28O14 | 726.2 | −8.147 | −8.191 | −8.191 | −46.82 |
4 | Leucocyanidin | C15H14O7 | 306.3 | −7.523 | −7.523 | −7.523 | −24.34 |
5 | Myricetin | C15H10O8 | 318.2 | −7.171 | −7.209 | −7.209 | −21.72 |
6 | Serotonin | C10H12N2O | 176.2 | −6.963 | −6.963 | −6.963 | −41.45 |
7 | Kaempferol-3-O- rutinoside | C27H30O15 | 594.5 | −6.555 | −6.584 | −6.584 | −64.73 |
Ref | Phenytoin | C15H12N2O2 | 252.3 | −6.660 | −7.022 | −7.022 | −25.80 |
Interaction Type | Interacting Residues | |
---|---|---|
Phenytoin | Polar Non-polar | Glu-942, Trp-1424, Met-1425 Ser-5, Lys-7, Trp-8, Arg-10, Asp-11, His-12, Trp-923, Arg-937, Glu-945, Phe-1421, Lys-1422, Gly-1423, Asp-1426, Tyr-1429, Gly-1715, Asp-1717, Gly-1718 |
Luteolin 7-O- rutinoside | Polar Non-polar | Ser-5, Ser-6, Lys-7, Asp-11, Glu-387, Gln-1709, Gly-1715, Gly-1718, Leu-1719 Trp-8, Arg-10, His-12, Gly-331, Asn-333, Asn-361, Asp-384, Phe-385, Trp-386, Asn-388, Gln-391, Trp-923, Arg-937, Glu-942, Glu-945, Lys-1422, Gly-1423, Met-1425, Asp-1426, Tyr-1429, Gly-1690, Phe-1695, Trp-1716, Asp-1717, Leu-1720 |
Pelargonidin-3-rhamnoside | Polar Non-polar | Asn-333, Arg-358, Tyr-362 Ser-6, Trp-8, His-12, Lys-323, Gln-332, Asp-334, Ala-335, Asn-361, Tyr-364, Phe-385, Asn-388, Lys-913, Ile-914, Ser-915, Asn-916, Asp-917, Asp-949, Glu-952 |
6-C-glucosyl-8-C-arabinosyl apigenin | Polar Non-polar | Trp-8, Lys-323, Asn-333, Asp-334, Arg-358, Asn-361, Asn-388, Asn-916 Ser-5, Ser-6, Lys-7, Cys-9, Lys-277, Asp-322, Ser-324, His-325, Phe-326, Gly-331, Gln-332, Leu-336, Asn-359, Pro-360, Tyr-362, Gly-363, Arg-379, Phe-385, Leu-392, Ser-915, Asp-917, Glu-945, Trp-948 |
Leucocyanidin | Polar Non-polar | Arg-10, Asp-11, Asp-384, Phe-385, Lys-1422, Asp-1426, Asp-1717 Lys-7, Trp-8, His-12, Trp-386, Glu-387, Trp-923, Arg-937, Glu-942, Trp-943, Glu-945, Gln-1417, Gly-1423, Trp-1424, Met-1425, Tyr-1429, Ala-1714, Gly-1715, Gly-1718 |
Myricetin | Polar Non-polar | Ser-5, Glu-942, Gly-1423, Asp-1426 Ser-6, Lys-7, Arg-10, Phe-385, Glu-387, Asn-388, Arg-937, Phe-1421, Lys-1422, Trp-1424, Met-1425, Tyr-1429, Gly-1715, Asp-1717, Gly-1718, Ala-1721 |
Serotonin | Polar Non-polar | Arg-10, Arg-922, Asp-1433 Asp-11, Ser-13, Arg-14, Cys-15, Cys-16, Phe-1363, His-1365, Met-1374, Val-1401, Met-1425, Asp-1426, Ile-1427, Tyr-1429, Ala-1430, Pro-1441, Lys-1442, Tyr-1443 |
Kaempferol-3-O- rutinoside | Polar Non-polar | Trp-8, Asp-334, Asn-359, Tyr-362, Asp-917, Asp-949 Cys-1, Cys-2, Cys-9, His-12, Ser-13, Lys-277, Phe-328, Asn-333, Ala-335, Arg-358, Pro-360, Asn-361, Gly-363, Tyr-364, Ile-914, Ser-915, Asn-916, Glu-952 |
Structure | Ligand | Hydrogen Bonding | Salt Bridges/(π-π)/(π-Cation)/π-Sigma Interactions | Other Hydrophobic Contacts | Van der Waals Interactions |
---|---|---|---|---|---|
Ref | Phenytoin | Lys-7, Glu-942, Trp-1424, Met-1425, Asp-1426 | Arg-10 (π-cation) | Tyr-1429 | Asp-11, Glu-945, Lys-1422, Gly-1423, Asp-1426, Asp-1717 |
1 | Luteolin 7-O-Rutinoside | Ser-5, Ser-6, Lys-7, Glu-387, Gly-1715, Gly-1718, Leu-1719 | Lys-7 (π-sigma) | Asp-384, Phe-385, Trp-386, Trp-923, Met-1425, Tyr-1429, Phe-1695, Gln-1709, Trp-1716 | Arg-10, Gly-331, Gln-332, Asn-333, Arg-937, Glu-942, Glu-945, Gly-1423, Asp-1426, Tyr-1429 |
2 | Pelargonidin-3-Rhamnoside | Ser-5, Glu-330, Tyr-362, Gly-1690, Asp-1692 | Trp-8 (π-π), Asn-333 (π-lone pair), Asp-334 (salt bridge), Arg-358, Tyr-362 (π-sigma) | Leu-329, Leu-336, Phe-385, Leu-392, Arg-395, Ile-914, Val-1689 | - |
3 | 6-C-Glucosyl-8-C-Arabinosyl Apigenin | Trp-8, Lys-323, Asn-333, Asp-334, Arg-358, Asn-361, Asn-388, Asn-916 | Trp-8 (π-π T-shaped stacking) | Pro-360, Tyr-362, Phe-385, Leu-392 | Lys-7, Ser-324, Gly-331, Gln-332, Asn-359, Gly-363 |
4 | Leucocyanidin | Asp-384, Glu-387, Asp-1426, Asp-1717 | Lys-7 (π-alkyl), Arg-10 (π-cation) | Phe-385, Trp-1424, Met-1425, Tyr-1429 | Gln-1417, Gly-1423 |
5 | Myricetin | Gly-1423, Asp-1717 | Lys-7 (π-cation/π -alkyl) | Phe-385, Trp-1424, Met-1425 | Arg-10, Arg-937, Glu-942, Lys-1422, Gly-1718 |
6 | Serotonin | Arg-10, Arg-922, Asp-1426 | Asp-1433 (salt bridge) | Cys-16, Met-1374, Val-1401, Tyr-1429, Ala-1430, Pro-1441, Tyr-1443 | Asp-11, Arg-14, His-1365 |
7 | Kaempferol-3-O-Rutinoside | Trp-8, Asp-334, Asn-359, Asn-361, Asp-917 | Arg-358 (π-cation) | Cys-1, Cys-2, Phe-328, Pro-360, Tyr-362, Ile-914, Asp-949 | His-12, Ile-914, Asn-916 |
Ligand | MW (g/mol) | HB Acceptor | HB Donor | Log P | Molar Refractivity | Rule of Five Violations | Bio- Availability Score | GI Absorption | BBB Permeation |
---|---|---|---|---|---|---|---|---|---|
Luteolin 7-O- rutinoside | 610.52 | 16 | 10 | 2.81 | 140.52 | 3 | 0.17 | Low | - |
Pelargonidin-3-rhamnoside | 417.39 | 9 | 6 | −1.61 | 105.11 | 1 | 0.55 | Low | - |
6-C-glucosyl-8-C-arabinosyl apigenin | 726.23 | 17 | 11 | 2.16 | 171.97 | 3 | 0.17 | Low | - |
Leucocyanidin | 306.27 | 7 | 6 | 1.19 | 75.50 | 1 | 0.55 | High | - |
Myricetin | 318.24 | 8 | 6 | 1.08 | 80.06 | 1 | 0.55 | Low | - |
Serotonin | 176.21 | 2 | 3 | 1.18 | 52.80 | 0 | 0.55 | High | + |
Kaempferol-3-O-rutinoside | 594.52 | 15 | 9 | 2.79 | 139.36 | 3 | 0.17 | Low | - |
Structure Number | Ligand | Predicted LD50 (mg/kg) | Predicted Toxicity Class | Carcinogenicity |
---|---|---|---|---|
1 | Luteolin-7-O-rutinoside | 5000 | 5 | - |
2 | Pelargonidin-3-rhamnoside | 5000 | 5 | - |
3 | 6-C-glucosyl-8-C- arabinosyl apigenin | 2300 | 5 | - |
4 | Leucocyanidin | 2500 | 5 | - |
5 | Myricetin | 159 | 3 | - |
6 | Serotonin | 2300 | 5 | - |
7 | Kaempferol-3-O-rutinoside | 5000 | 5 | - |
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Ashraf, A.; Ahmed, A.; Juffer, A.H.; Carter, W.G. An In Vivo and In Silico Approach Reveals Possible Sodium Channel Nav1.2 Inhibitors from Ficus religiosa as a Novel Treatment for Epilepsy. Brain Sci. 2024, 14, 545. https://doi.org/10.3390/brainsci14060545
Ashraf A, Ahmed A, Juffer AH, Carter WG. An In Vivo and In Silico Approach Reveals Possible Sodium Channel Nav1.2 Inhibitors from Ficus religiosa as a Novel Treatment for Epilepsy. Brain Sciences. 2024; 14(6):545. https://doi.org/10.3390/brainsci14060545
Chicago/Turabian StyleAshraf, Aqsa, Abrar Ahmed, André H. Juffer, and Wayne G. Carter. 2024. "An In Vivo and In Silico Approach Reveals Possible Sodium Channel Nav1.2 Inhibitors from Ficus religiosa as a Novel Treatment for Epilepsy" Brain Sciences 14, no. 6: 545. https://doi.org/10.3390/brainsci14060545
APA StyleAshraf, A., Ahmed, A., Juffer, A. H., & Carter, W. G. (2024). An In Vivo and In Silico Approach Reveals Possible Sodium Channel Nav1.2 Inhibitors from Ficus religiosa as a Novel Treatment for Epilepsy. Brain Sciences, 14(6), 545. https://doi.org/10.3390/brainsci14060545