Computational Study on Selective PDE9 Inhibitors on PDE9-Mg/Mg, PDE9-Zn/Mg, and PDE9-Zn/Zn Systems
Abstract
:1. Introduction
2. Materials and Methods
2.1. Protein Preparation
2.2. Ligand Topology
2.3. Molecular Docking
2.4. Molecular Dynamics Simulations
2.5. MM/PBSA Binding Free Energy Calculation
3. Results and Discussion
3.1. Docking of PDE-9 Inhibitors with PDE-9
3.2. Interaction Details Based on the Simulation Results
3.2.1. Compound 1 (BAY73-6691 -R and S) in PDE-9 Zn/Mg, PDE-9 Mg/Mg, and PDE-9 Zn/Zn
3.2.2. Compound 2 (28R and 28S) in PDE-9 Zn/Mg, PDE-9 Mg/Mg, and PDE-9 Zn/Zn
3.2.3. Compound 3 (3R and 3S) in PDE-9 Zn/Mg, PDE-9 Mg/Mg, and PDE-9 Zn/Zn
3.2.4. Compound 4 (PF-04447943) in PDE-9 Zn/Mg, PDE-9 Mg/Mg, and PDE-9 Zn/Zn
3.2.5. Compound 5 (PF-4181366) in PDE-9 Zn/Mg, PDE-9 Mg/Mg and PDE-9 Zn/Zn
3.2.6. Compound 6 (4r) in PDE-9 Zn/Mg, PDE-9 Mg/Mg and PDE-9 Zn/Zn
4. 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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Compound ID | Enantiomer | Docking Score (kcal/mol) | Interacting Residues * |
---|---|---|---|
Compound 1 | R | −9.5 | F251, Q453, F456 |
Compound 1 | S | −9.5 | F251, Q453, F456 |
Compound 2 | R | −11.3 | F251, A452, Q453, F456 |
Compound 2 | S | −10.9 | A452, Q453, F456 |
Compound 3 | R | −10.7 | F251, Y424, Q453, F456 |
Compound 3 | S | −10.3 | A452, Q453, F456 |
Compound 4 | n/a | −10.7 | F251, Q453, F456 |
Compound 5 | n/a | −12.0 | F251, Q453, F456 |
Compound 6 | n/a | −9.3 | A452, Q453, F456 |
Compound ID/Enantiomer | Metal System | Hydrogen Bond Interactions | Hydrophobic Contacts |
---|---|---|---|
Compound 1 (R) | Zn/Mg | Q453 | F456 |
Mg/Mg | Q453 | F456 | |
Zn/Zn | Q453 | F456 | |
Compound 1 (S) | Zn/Mg | Q453 | F456 |
Mg/Mg | Q453, N405 | F456 | |
Zn/Zn | Q453 | No Interactions | |
Compound 2 (R) | Zn/Mg | Q453, A452, N405 | F456 |
Mg/Mg | Q453, A452 | F456 | |
Zn/Zn | Q453, A452 | Y424 | |
Compound 2 (S) | Zn/Mg | Q453, Y424 | F456, H368 |
Mg/Mg | Q453, A452 | F456, H368 | |
Zn/Zn | Q453, A452 | F456 | |
Compound 3 (R) | Zn/Mg | T302 | Y424, F441 |
Mg/Mg | No Interactions | No Interactions | |
Zn/Zn | Q453 | F456 | |
Compound 3 (S) | Zn/Mg | Q453, A452 | F456 |
Mg/Mg | Q453, A452, Y424 | F456 | |
Zn/Zn | Y424, A452, F456 | F456 | |
Compound 4 | Zn/Mg | Q453 | F456, F441 |
Mg/Mg | No Interactions | F456 | |
Zn/Zn | Q453 | F456 | |
Compound 5 | Zn/Mg | No Interactions | No Interactions |
Mg/Mg | A452 | F441 | |
Zn/Zn | A452 | F456, F441 | |
Compound 6 | Zn/Mg | Q453, A452 | F456 |
Mg/Mg | Q453, A452 | F456 | |
Zn/Zn | Q453, A452 | F456 |
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Sivakumar, D.; Mudedla, S.; Jang, S.; Kim, H.; Park, H.; Choi, Y.; Oh, J.; Wu, S. Computational Study on Selective PDE9 Inhibitors on PDE9-Mg/Mg, PDE9-Zn/Mg, and PDE9-Zn/Zn Systems. Biomolecules 2021, 11, 709. https://doi.org/10.3390/biom11050709
Sivakumar D, Mudedla S, Jang S, Kim H, Park H, Choi Y, Oh J, Wu S. Computational Study on Selective PDE9 Inhibitors on PDE9-Mg/Mg, PDE9-Zn/Mg, and PDE9-Zn/Zn Systems. Biomolecules. 2021; 11(5):709. https://doi.org/10.3390/biom11050709
Chicago/Turabian StyleSivakumar, Dakshinamurthy, Sathishkumar Mudedla, Seonghun Jang, Hyunjun Kim, Hyunjin Park, Yonwon Choi, Joongyo Oh, and Sangwook Wu. 2021. "Computational Study on Selective PDE9 Inhibitors on PDE9-Mg/Mg, PDE9-Zn/Mg, and PDE9-Zn/Zn Systems" Biomolecules 11, no. 5: 709. https://doi.org/10.3390/biom11050709
APA StyleSivakumar, D., Mudedla, S., Jang, S., Kim, H., Park, H., Choi, Y., Oh, J., & Wu, S. (2021). Computational Study on Selective PDE9 Inhibitors on PDE9-Mg/Mg, PDE9-Zn/Mg, and PDE9-Zn/Zn Systems. Biomolecules, 11(5), 709. https://doi.org/10.3390/biom11050709