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Antiviral drug acyclovir exhibits antitumor activity via targeting βTrCP1: Molecular docking and dynamics simulation
Shagufta Shafique1, Sajid Rashid1
1National Centre for Bioinformatics, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
Abstract:
The critical role of βTrCP1 in cancer development makes it a discerning target for the development of small drug like molecules. Currently, no inhibitor exists that is able to target its substrate binding site. Through molecular docking and dynamics simulation assays, we explored the comparative binding pattern of βTrCP1-WD40 domain with ACV and its phospho-derivatives (ACVMP, ACVDP and ACVTP). Consequently, through principal component analysis, βTrCP1-ACVTP was found to be more stable complex by obscuring a reduced conformational space than other systems. Thus based on the residual contribution and hydrogen bonding pattern, ACVTP was considered as a noteworthy inhibitor which demarcated binding in the cleft formed by βTrCP1-WD40 specific β-propeller. The outcomes of this study may provide a platform for rational design of specific and potent inhibitor against βTrCP1, with special emphasis on anticancer activity.
Insights
Researchers identified ACVTP as a promising inhibitor targeting the beta-transducin repeat-containing protein 1 (βTrCP1) substrate binding site. This discovery offers a new avenue for developing potent anticancer drugs by stabilizing the βTrCP1-WD40 domain complex.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- The beta-transducin repeat-containing protein 1 (βTrCP1) is crucial in cancer development.
- Targeting βTrCP1 with small molecules is a promising anticancer strategy.
- Currently, no inhibitors effectively target the βTrCP1 substrate binding site.
Purpose of the Study:
- To explore the binding patterns of βTrCP1-WD40 domain with ACV and its phospho-derivatives.
- To identify a stable and potent inhibitor for the βTrCP1 substrate binding site.
- To provide a basis for designing specific βTrCP1 inhibitors for anticancer applications.
Main Methods:
- Molecular docking simulations.
- Molecular dynamics simulations.
- Principal component analysis (PCA).
Main Results:
- ACVTP formed a more stable complex with the βTrCP1-WD40 domain compared to ACV, ACVMP, and ACVDP.
- PCA revealed that ACVTP reduced the conformational space, indicating enhanced stability.
- ACVTP binding occurred within the cleft of the βTrCP1-WD40 domain's β-propeller structure, supported by residual contribution and hydrogen bonding analysis.
Conclusions:
- ACVTP is a noteworthy inhibitor candidate for the βTrCP1-WD40 domain.
- The study provides a rational design strategy for developing specific and potent βTrCP1 inhibitors.
- These findings have significant implications for anticancer drug development targeting βTrCP1.
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