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In silico Investigations of the Mode of Action of Novel Colchicine Derivatives Targeting ?-Tubulin Isotypes: A Search for a Selective and Specific ?-III Tubulin Ligand.

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 ?III 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 ?III. 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 ?III. These compounds were screened and ranked based on their binding affinity and conformational stability in the colchicine binding site of tubulin ?III. 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 ?-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.

SUBMITTER: Pallante L

PROVIDER: S-EPMC7047339 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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<i>In silico</i> Investigations of the Mode of Action of Novel Colchicine Derivatives Targeting β-Tubulin Isotypes: A Search for a Selective and Specific β-III Tubulin Ligand.

Pallante Lorenzo L Rocca Antonio A Klejborowska Greta G Huczynski Adam A Grasso Gianvito G Tuszynski Jack A JA Deriu Marco A MA

Frontiers in chemistry 20200221

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-tumora ...[more]

PMID: 32154219

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Project description:BACKGROUND: Anti-mitotic compounds (microtubule de-stabilizers) such as vincristine and vinblastine have been shown clinically successful in treating various cancers. However, development of drug-resistance cells limits their efficacies in clinical situations. Therefore, experiments were performed to determine possible drug resistance mechanisms related to the application of anti-mitotic cancer therapy. PRINCIPAL FINDINGS: A KB-derived microtubule de-stabilizer-resistant KB-L30 cancer cell line was generated for this study. KB-L30 cells showed cross-resistance to various microtubule de-stabilizers including BPR0L075, vincristine and colchicine through multiple-drug resistant (MDR)-independent mechanisms. Surprisingly, KB-L30 cells showed hyper-sensitivity to the microtubule-stabilizer, paclitaxel. Results of the RT-PCR analysis revealed that expression of both class II and III ?-tubulin was down-regulated in KB-L30 cells as compared to its parental KB cancer cells. In addition, DNA sequencing analysis revealed six novel mutation sites present in exon four of the ?I-tubulin gene. Computational modeling indicated that a direct relationship exists between ?I-tubulin mutations and alteration in the microtubule assembly and dynamic instability in KB-L30 cells and this predicted model was supported by an increased microtubule assembly and reduced microtubule dynamic instability in KB-L30 cells, as shown by Western blot analysis. CONCLUSIONS AND SIGNIFICANCE: Our study demonstrated that these novel mutations in exon four of the ?I-tubulin induced resistance to microtubule de-stabilizers and hyper-sensitivity to microtubule stabilizer through an alteration in the microtubule assembly and dynamics in cancer cells. Importantly, the current study reveals that cancer cells may acquire drug resistance ability to anti-mitotic compounds through multiple changes in the microtubule networks. This study further provided molecular information in drug selection for patients with specific tubulin mutations.

Dataset Information

In silico Investigations of the Mode of Action of Novel Colchicine Derivatives Targeting ?-Tubulin Isotypes: A Search for a Selective and Specific ?-III Tubulin Ligand.

Publications

<i>In silico</i> Investigations of the Mode of Action of Novel Colchicine Derivatives Targeting β-Tubulin Isotypes: A Search for a Selective and Specific β-III Tubulin Ligand.

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