Effects of vinblastine and its metabolites on nausea and alopecia associated receptors

The effects of vinblastine (VLB) and its thirty-five known metabolites were investigated on nausea and alopecia associated receptors by means of molecular docking simulations. The in silico pharmacokinetics (PK) properties and binding affinities of VLB and its metabolites with the vinca site of tubulin were also elucidated in the present study. VLB and its metabolites have demonstrated binding affinities mainly for the muscarinic receptors M₁, M₄ and M₅ that display significant roles in the onset of nausea during chemotherapy. The metabolites of VLB interact with the binding site of acetylcholine and share similar binding interactions with residues involved with the endogenous substrate. Furthermore, VLB metabolites have also shown binding affinities for alopecia associated receptors such as vitamin D (VDR), androgen, smoothened and MDM2, which can trigger the death of hair follicle following cancer treatment. The predicted PK properties of VLB and its metabolites have revealed that they are all substrates and inhibitors of CYP3A4 and P-glycoprotein, and inhibitors of CYP2D6. The majority of metabolites do not cross the blood-brain barrier, do not undergo glucuronidation and have no affinity for the human ether-à-go-go-related gene receptor. Finally, VLB metabolites docked into the vinca site of tubulin have revealed that metabolites 8, 10 and 11 have binding affinities for tubulin and interact with the same residues involved with VLB. Taking into account the PK properties, metabolite 10 (20-Hydroxy-VLB) has shown to be a potential active analog of VLB. This research project has aimed to a better understanding of the VLB-induced off-targets events such as nausea and alopecia, and how the VLB metabolites can trigger these ADRs. These findings suggest that knowing which and how the metabolites of VLB are involved with off-targets receptors of nausea and alopecia, as well as their PK properties and effects on tubulin target, ADRs during chemotherapy could be eliminated or lessened. This is possible if modifications on the chemical structure of VLB and advances in drug discovery and medicinal chemistry fields are taken into consideration in future studies. It would enhance target specificity as it could decrease formation of many metabolites and hence minimize the number of off-target interactions. That could result in providing a less unpleasant treatment for cancer patients and a higher quality of life during chemotherapy

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

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