In Silico Analysis of Mechanisms of Maribavir-Induced Inhibition and Drug Resistance Mutations in pUL97 Kinase Structural Prediction with AlphaFold2
Abstract
1. Introduction
2. Materials and Methods
2.1. Prediction of pUL97 Protein Structure
2.2. Quality Assessment of Predicted pUL97 Protein Structure
2.3. Docking of ATP and Antiviral Drugs to the Predicted pUL97 Protein Structure
2.4. Generation of Mutant pUL97 Homology Models
3. Results and Discussion
3.1. Conserved Structural Sub-Domains and Functional Domains of pUL97 Kinase
3.2. Functional Differences Between Cellular Protein Kinases and Viral pUL97 Kinase
3.3. Docking of ATP and Antiviral Drugs to Predicted pUL97 Protein Structure
3.3.1. Docking of ATP to pUL97 Kinase
3.3.2. Docking of GCV and CPV to pUL97 Kinase
3.3.3. Docking of MBV to pUL97 Kinase
3.4. Insights into the Mechanisms of MBV-Induced Inhibition of pUL97 Kinase Activity
3.5. Amino Acid Substitutions Conferring Resistance to Maribavir
3.6. Amino Acid Substitutions Conferring Hyperscuceptibility to Maribavir
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
a.a. | Amino acid |
AI | Artificial intelligence |
ATP | Adenosine triphosphate |
cAPK | Cyclic AMP-dependent protein kinase |
CDK | Cyclin-dependent kinase |
CMV | Cytomegalovirus |
CPV | Cyclopropavir |
EC50 | Effective concentration of antiviral that reduces the viral growth by 50% |
GCN2 | General control kinase 2 |
GCV | Ganciclovir |
GLIDE | Grid-based ligand docking with energetics |
Ki | Inhibition constant |
I-TASSER | Iterative threading assembly refinement |
MBV | Maribavir |
MSA | Multiple sequence alignment |
NEC | Nuclear egress complex |
NLS | Nuclear localization signal |
PAE | Predicted aligned error |
pLDDT | Predicted local distance difference test |
rb | Retinoblastoma |
RS | Regulatory spine |
SH | Shell |
SLiM | Short linear motif |
SRPK1 | Serine–arginine protein kinase 1 |
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Amino Acid Changes | Fold Change Maribavir | Fold Change Ganciclovir | Viral Growth | Clinical/Lab-derived | Structural Representation * | References |
---|---|---|---|---|---|---|
First cluster of amino acid substitutions conferring drug resistance | ||||||
T409M | 81× | 0.9× | No change | Clinical | Figure 5 | [91] |
H411L | 69× | 0.7× | ND | Clinical | Figure 5 | [67] |
H411N | 9× | 1.0× | ND | Clinical | Figure 5 | [67] |
H411Y | 12× | 0.5× | No change | Clinical | Figure 5 | [67,92] |
L397R | 200× | 1.6× | No change | Lab-derived | Figure S10 | [91] |
L337M | 3.5× | 1.0× | No change | Lab-derived | Figure S10 | [93] |
V353A | 15× | 1.0–1.5× | No change | Lab-derived | Figure S11 | [91] |
V356G | 108× | 5.5× | Moderately decreased | Lab-derived | Figure S11 | [94] |
C480F | 224× | 2.3× | Moderately decreased | Clinical | Figure 6 | [95] |
C480R | 243× | 9.0× | Markedly decreased | Clinical | Figure 6 | [96] |
Second cluster of amino acid substitutions conferring drug resistance | ||||||
D456N | 278× | 12× | Markedly decreased | Lab-derived | Figure S12 | [96] |
P521L | 428× | 17× | Markedly decreased | Clinical | Figure S12 | [94] |
V466G | 321× | 11× | Markedly decreased | Clinical | Figure S12 | [94,97] |
F342Y | 4.5× | 6× | No change | Clinical | Figure 7 | [68] |
F342S | 18× | 7.8× | Moderately decreased | Lab-derived | Figure 7 | [94] |
Amino acid substitutions conferring hypersusceptibility to maribavir | ||||||
V345I | 0.4× | 1.3× | ND | Clinical | Figure S13 | [98] |
M460I | 0.2× | 12× | ND | Clinical | Figure S13 | [99,100] |
M460V | 0.3× | 9.1× | No change | Clinical | Figure S13 | [91,92,100] |
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Piret, J.; Boivin, G. In Silico Analysis of Mechanisms of Maribavir-Induced Inhibition and Drug Resistance Mutations in pUL97 Kinase Structural Prediction with AlphaFold2. Viruses 2025, 17, 941. https://doi.org/10.3390/v17070941
Piret J, Boivin G. In Silico Analysis of Mechanisms of Maribavir-Induced Inhibition and Drug Resistance Mutations in pUL97 Kinase Structural Prediction with AlphaFold2. Viruses. 2025; 17(7):941. https://doi.org/10.3390/v17070941
Chicago/Turabian StylePiret, Jocelyne, and Guy Boivin. 2025. "In Silico Analysis of Mechanisms of Maribavir-Induced Inhibition and Drug Resistance Mutations in pUL97 Kinase Structural Prediction with AlphaFold2" Viruses 17, no. 7: 941. https://doi.org/10.3390/v17070941
APA StylePiret, J., & Boivin, G. (2025). In Silico Analysis of Mechanisms of Maribavir-Induced Inhibition and Drug Resistance Mutations in pUL97 Kinase Structural Prediction with AlphaFold2. Viruses, 17(7), 941. https://doi.org/10.3390/v17070941