A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials for Biological Testing (Cell Culture)
2.2. Protein Synthesis Assay
2.3. Statistical Methods for Analysis of Protein Synthesis Data
2.4. Molecular Modeling Methods—Evaluate Shape Fitting Algorithms
2.5. Evaluate De Novo Ligand Generation for AA Analogues
2.6. Molecular Dynamics Simulations
3. Results
3.1. Virtual Screening of AA and AA Analogues on Ribosomal A-Site Peptidyl Transferase Center
3.2. Ribosomal Docking Reveals that Therapeutically Active AA Analogues Possess Strong Ribosomal Binding Capacity
3.3. Structural Basis for Drug-Ribosome Interactions (3D-QSAR) Identifies Key Fingerprint Features (2D-Ligand Interaction Maps)
3.4. Modeling Shows Structural Underpinnings for Drug-Ribosome Interaction for AA Analogues
3.5. CEAA is an Inhibitor of Protein Synthesis
4. Discussion
4.1. Ribosomal Binding Capacity of CEAA Correlates with Inhibition of Protein Synthesis
4.2. Structural Modifications of AA
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Name | Structure | Predicted CSM Affinity (-log10(KD|Ki)) | Docking score (ΔG) | Conformation 1 Predicted MM-GBSA Affinity (ΔG) | Conformation 2 Predicted MM-GBSA Affinity (ΔG) |
---|---|---|---|---|---|
CEAA | −11.1 | −6.8 | −50.81 | −32.52 | |
AA | −10.8 | −4.59 | −48.12 | −21.33 | |
CAA | −10.9 | −6.65 | −32.92 | −16.3 | |
DCEAA | −10.5 | −6.13 | −15.32 | −15.42 | |
PAA | −10.4 | −5.62 | −25.95 | 77.85 | |
EAA | −10.5 | −4.24 | 1293.69 | 3472.33 | |
DeBAA | −10.1 | −4.16 | 933.01 | 49.55 | |
DeBEAA | −9.4 | −4.38 | 1279.36 | 2815.08 |
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Caulfield, T.R.; Hayes, K.E.; Qiu, Y.; Coban, M.; Seok Oh, J.; Lane, A.L.; Yoshimitsu, T.; Hazlehurst, L.; Copland, J.A.; Tun, H.W. A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor. Biomolecules 2020, 10, 1407. https://doi.org/10.3390/biom10101407
Caulfield TR, Hayes KE, Qiu Y, Coban M, Seok Oh J, Lane AL, Yoshimitsu T, Hazlehurst L, Copland JA, Tun HW. A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor. Biomolecules. 2020; 10(10):1407. https://doi.org/10.3390/biom10101407
Chicago/Turabian StyleCaulfield, Thomas R., Karen E. Hayes, Yushi Qiu, Mathew Coban, Joon Seok Oh, Amy L. Lane, Takehiko Yoshimitsu, Lori Hazlehurst, John A. Copland, and Han W. Tun. 2020. "A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor" Biomolecules 10, no. 10: 1407. https://doi.org/10.3390/biom10101407