Abstract
The cardinal role of microtubules in cell mitosis makes them interesting drug targets for many pharmacological treatments, including those against cancer. Moreover, different expression patterns between cell types for several tubulin isotypes represent a great opportunity to improve the selectivity and specificity of the employed drugs and to design novel compounds with higher activity only on cells of interest. In this context, tubulin isotype βIII represents an excellent target for anti-tumoral therapies since it is overexpressed in most cancer cells and correlated with drug resistance. Colchicine is a well-known antimitotic agent, which is able to bind the tubulin dimer and to halt the mitotic process. However, it shows high toxicity also on normal cells and it is not specific for isotype βIII. In this context, the search for colchicine derivatives is a matter of great importance in cancer research. In this study, homology modeling techniques, molecular docking, and molecular dynamics simulations have been employed to characterize the interaction between 55 new promising colchicine derivatives and tubulin isotype βIII. These compounds were screened and ranked based on their binding affinity and conformational stability in the colchicine binding site of tubulin βIII. Results from this study point the attention on an amide of 4-chlorine thiocolchicine. This colchicine-derivative is characterized by a unique mode of interaction with tubulin, compared to all other compounds considered, which is primarily characterized by the involvement of the α-T5 loop, a key player in the colchicine binding site. Information provided by the present study may be particularly important in the rational design of colchicine-derivatives targeting drug resistant cancer phenotypes.
Highlights
The pivotal role of microtubules (MTs) in the mitotic process make them important targets for anticancer therapies since cancerous cells proliferate by unregulated cell division (Gajewski et al, 2013)
55 colchicine derivatives were screened for their binding properties to tubulin isotype βIII
After the docking of all compounds to the target isotype of tubulin, a molecular dynamics simulation of 1 ns was performed on each generated receptor-ligand complex
Summary
The pivotal role of microtubules (MTs) in the mitotic process make them important targets for anticancer therapies since cancerous cells proliferate by unregulated cell division (Gajewski et al, 2013). Several studies in the past have proposed less toxic colchicine derivatives as an alternative to colchicine (Lu et al, 2012; Wang et al, 2016; Johnson et al, 2017; Majcher et al, 2018a,b; Klejborowska et al, 2019) These novel colchicine derivatives may be designed to show high specificity only for tubulin isotypes, which are over-expressed in cancer, in order to maximize their effect only on tumor cells and reduce side effects of the drug due to its toxicity on normal cells (Lu and Luduena, 1994; Luduena et al, 1995)
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