Interdomain Twists of Human Thymidine Phosphorylase and its Active-Inactive Conformations: Binding of 5-FU and its Analogues to hTP vs. DPD

Alisaraie, Laleh and Tozer, Tiffany and Heale, Kali and Chagas, Caroline Manto and de Barros, Andre Luis Branco (2019) Interdomain Twists of Human Thymidine Phosphorylase and its Active-Inactive Conformations: Binding of 5-FU and its Analogues to hTP vs. DPD. Chemical Biology and Drug Design, 94 (5). pp. 1956-1972. ISSN 1747-0285

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Abstract

5‐fluorouracil (5‐FU) is an anticancer drug, which inhibits human thymidine phosphorylase (hTP) and plays a key role in maintaining the process of DNA replication and repair. It is involved in regulating pyrimidine nucleotide production, by which it inhibits the mechanism of cell proliferation and cancerous tumor growth. However, up to 80% of the administered drug is metabolized by dihydropyrimidine dehydrogenase (DPD). This work compares binding of 5‐FU and its analogues to hTP and DPD, and suggests strategies to reduce drug binding to DPD to decrease the required dose of 5‐FU. An important feature between the proteins studied here was the difference of charge distribution in their binding sites, which can be exploited for designing drugs to selectively bind to the hTP. The 5‐FU presence was thought to be required for a closed conformation. Comparison of the calculation results pertaining to unliganded and liganded protein showed that hTP could still undergo open–closed conformations in the absence of the ligand; however, the presence of a positively charged ligand better stabilizes the closed conformation and rigidifies the core region of the protein more than unliganded or neutral liganded system. The study has also shown that one of the three hinge segments linking the two major α and α/β domains of the hTP is an important contributing factor to the enzyme's open–close conformational twist during its inactivation–activation process. In addition, the angle between the α/β‐domain and the α‐domain has shown to undergo wide rotations over the course of MD simulation in the absence of a phosphate, suggesting that it contributes to the stabilization of the closed conformation of the hTP.

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