Vinblastine (VLB) is a vinca alkaloid drug that inhibits the polymerization of microtubules (MTs) and promotes cell arrest. VLB causes a variety of adverse drug reactions (ADRs). Our research results show that it mainly affects the gastrointestinal tract, myeloid tissue and hair follicle pathways. Similar to many other anticancer drugs, VLB has been strongly associated with nausea. Despite advances in the medicinal chemistry field that aims to reduce drug toxicity, the cause and mechanism of VLB-induced ADRs remain poorly understood. ADRs are complex and sometimes considered idiosyncratic events, however, there is a strong relationship among drug metabolites and ADRs. I have found that VLB can be metabolized into 35 metabolites, whose effects concerning nausea associated receptors have not yet been characterized. We have recently identified major receptors associated with nausea protein interaction network that includes histaminic, dopaminergic and muscarinic receptors. Utilizing molecular docking approach as well as an accurate in silico pharmacological property-predictor, my research unveiled potential interactions of the VLB metabolites with our identified off-targets sites. We have found that despite weak affinities of the majority of the metabolites for histaminic H1 and H3, and dopaminergic D2 receptors, they have strong interactions with muscarinic M1, M4 and M5 receptors. Interestingly, VLB has a better binding affinity than the natural substrate acetylcholine for M5R. Molecular docking of VLB and metabolites into the drug’s binding site, at the interface of α- and β-tubulin, demonstrates that metabolite 20-Hydroxy-VLB has stronger binding affinity (-13.4 kJ/mol) than VLB (-11.2 kJ/mol) for tubulin. They, as well, show similar pharmacological properties. These novel findings provide knowledge of which VLB metabolites are likely to be associated with nausea during chemotherapy, as well as their binding interactions with the receptors involved in this pathway. By precisely determining the mechanism of VLB and metabolites interaction with the off-targets sites, ADRs such as nausea can be avoided. Furthermore, our lab has demonstrated the possibility of VLB delivery by single-walled carbon nanotubes (SWNT) due to their strong drug-carrier interactions. This study proposes effective modifications on the chemical structure of VLB that along with applications of nanoparticles for its delivery could result in reducing ADRs.

Vinblastine and effects of its metabolites on nausea associated receptors

256th National Meeting (2018)

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