Sarcorucinine-D Inhibits Cholinesterases and Calcium Channels: Molecular Dynamics Simulation and In Vitro Mechanistic Investigations
Abstract
:1. Introduction
2. Results and Discussion
2.1. Inhibition Kinetics of AChE and BChE
2.2. Molecular Docking Investigations against AChE
2.3. MD Analysis of Sarcorucinine-D in the Vicinity of AChE
2.4. AChE Deviation and Fluctuation in the Context of Sarcorucinine-D
2.5. Protein–Ligand Interaction Contact Analyses
2.6. Molecular Investigation of Sarcorucinine-D’s Properties as an AChE Inhibitor
2.7. Pre- and Post-MD Results
2.8. Antispasmodic and Ca2+ Channel-Blocking (CCB) Properties
2.9. Cytotoxicity Evaluation
3. Material and Methods
3.1. Enzyme Inhibition Assays
3.2. Estimation of Inhibition and Kinetic Parameters
3.3. Molecular Ligand–Protein Docking
3.4. Molecular Dynamic Simulation Set-Up
3.5. Antispasmodic Activity in Isolated Rabbit Jejunum
3.6. Determination of Calcium Antagonist Activity
3.7. Cytotoxicity Evaluation
3.8. Statistical Analysis
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Compound | Acetylcholinesterase | Butyrylcholinesterase | ||||
IC50 (µM)a | Ki b (µM)a | Inhibition | IC50 (µM)a | Ki (µM)a | Inhibition c | |
Sarcorucinine-D | 42.9 ± 3.13 | 103.3 ± 6.67 | NC | 8.87 ± 0.56 | 4.66 ± 0.3 | NC |
Tacrine | 0.021 ± 0.002 | 0.23 ± 0.02 | MT | 0.051 ± 0.005 | 0.025 ± 0.003 | MT |
Galanthamine | 0.45 ± 0.02 | 0.19 ± 0.01 | MT | 39.1 ± 0.032 | 32.0 ± 0.33 | NC |
Binding energy (kcal/mol) a | −12.73 | |
Estimated Ki b | 4.66 × 10−10 | |
Compl. values c | 0.53 | |
Solv. accessible surface d | 45.1/564.4 | |
Residues involved in specific contacts with Sarcorucinine-D e | polar contacts (Enz-Inh.) | Glu199 (O…O-H) Inh. (2.7Å) Tyr130 (O-H…O) Inh. (2.8Å) |
non-polar contacts | Tyr70; Asp72; Trp84; Ser122; Leu127; Trp279; Phe290; Phe330; Phe331; Tyr334; His440; Ile444 | |
destabilizing contacts | Asp72; Trp84; Gly117; Gly118; Ser122; Gly123; Tyr130; Glu199; Ser200; Phe330; Tyr334; His440; Ile444 |
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Khalid, A.; Abdalla, M.; Saeed, M.; Ghayur, M.N.; Kalauni, S.K.; Albratty, M.; Alhazmi, H.A.; Mesaik, M.A.; Gilani, A.H.; Ul-Haq, Z. Sarcorucinine-D Inhibits Cholinesterases and Calcium Channels: Molecular Dynamics Simulation and In Vitro Mechanistic Investigations. Molecules 2022, 27, 3361. https://doi.org/10.3390/molecules27113361
Khalid A, Abdalla M, Saeed M, Ghayur MN, Kalauni SK, Albratty M, Alhazmi HA, Mesaik MA, Gilani AH, Ul-Haq Z. Sarcorucinine-D Inhibits Cholinesterases and Calcium Channels: Molecular Dynamics Simulation and In Vitro Mechanistic Investigations. Molecules. 2022; 27(11):3361. https://doi.org/10.3390/molecules27113361
Chicago/Turabian StyleKhalid, Asaad, Mohnad Abdalla, Maria Saeed, Muhammad Nabeel Ghayur, Surya Kant Kalauni, Mohammed Albratty, Hassan A. Alhazmi, Mohammed Ahmed Mesaik, Anwarul Hassan Gilani, and Zaheer Ul-Haq. 2022. "Sarcorucinine-D Inhibits Cholinesterases and Calcium Channels: Molecular Dynamics Simulation and In Vitro Mechanistic Investigations" Molecules 27, no. 11: 3361. https://doi.org/10.3390/molecules27113361