Binding Pattern and Structural Interactome of the Anticancer Drug 5-Fluorouracil: A Critical Review
En-Shyh Lin1, Cheng-Yang Huang2,3
1Department of Beauty Science, National Taichung University of Science and Technology, Taichung City 403, Taiwan.
Abstract:
5-Fluorouracil (5-FU) stands as one of the most widely prescribed chemotherapeutics. Despite over 60 years of study, a systematic synopsis of how 5-FU binds to proteins has been lacking. Investigating the specific binding patterns of 5-FU to proteins is essential for identifying additional interacting proteins and comprehending their medical implications. In this review, an analysis of the 5-FU binding environment was conducted based on available complex structures. From the earliest complex structure in 2001 to the present, two groups of residues emerged upon 5-FU binding, classified as P- and R-type residues. These high-frequency interactive residues with 5-FU include positively charged residues Arg and Lys (P type) and ring residues Phe, Tyr, Trp, and His (R type). Due to their high occurrence, 5-FU binding modes were simplistically classified into three types, based on interactive residues (within <4 Å) with 5-FU: Type 1 (P-R type), Type 2 (P type), and Type 3 (R type). In summary, among 14 selected complex structures, 8 conform to Type 1, 2 conform to Type 2, and 4 conform to Type 3. Residues with high interaction frequencies involving the N1, N3, O4, and F5 atoms of 5-FU were also examined. Collectively, these interaction analyses offer a structural perspective on the specific binding patterns of 5-FU within protein pockets and contribute to the construction of a structural interactome delineating the associations of the anticancer drug 5-FU.
Insights
This review details how the chemotherapy drug 5-Fluorouracil (5-FU) binds to proteins, identifying key P-type and R-type residues. Understanding these 5-FU protein interactions aids in discovering new therapeutic targets.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- 5-Fluorouracil (5-FU) is a widely used chemotherapy agent with over 60 years of clinical application.
- A comprehensive understanding of 5-FU's protein binding interactions remains incomplete.
- Identifying specific protein binding patterns is crucial for understanding its mechanism and potential new therapeutic applications.
Purpose of the Study:
- To systematically review and analyze the binding patterns of 5-Fluorouracil (5-FU) with proteins.
- To classify 5-FU binding modes based on interacting amino acid residues.
- To provide a structural basis for the interactions of 5-FU with its protein targets.
Main Methods:
- Analysis of available protein-ligand complex structures containing 5-FU.
- Classification of interacting amino acid residues into P-type (positively charged: Arg, Lys) and R-type (aromatic: Phe, Tyr, Trp, His).
- Categorization of 5-FU binding modes into three types based on residue interactions within 4 Å.
Main Results:
- Two primary groups of residues, P-type and R-type, were identified as frequently interacting with 5-FU.
- 5-FU binding modes were classified into Type 1 (P-R type), Type 2 (P type), and Type 3 (R type).
- Out of 14 analyzed structures, 8 were Type 1, 2 were Type 2, and 4 were Type 3, with specific 5-FU atoms (N1, N3, O4, F5) showing high interaction frequencies.
Conclusions:
- The study establishes a classification system for 5-FU protein binding modes based on structural analysis.
- Identified P-type and R-type residues and their interaction patterns offer insights into 5-FU's binding preferences.
- This structural interactome analysis contributes to a deeper understanding of 5-FU's molecular interactions and potential for drug development.
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