In silico 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; Rocca, Antonio; Klejborowska, Greta; Huczyński, Adam; Grasso, Gianvito; Tuszyński, Jack A.; Deriu, Marco Agostino

doi:10.3389/fchem.2020.00108

Cited by 16 publications

(13 citation statements)

References 61 publications

(77 reference statements)

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“…We observed that, gloriosine was interacting with the α-T5 loop (comprising of residues 178–180 of the α-tubulin) in a similar way as colchicine. Identification and characterization of such interactions in other colchicine derivatives can be path-breaking 16 . The role of α-T5 loop of colchicine and its derivatives is associated with the better binding energies of their interaction and stabilization with tubulin heterodimer 16 , 17 .…”

Section: Resultsmentioning

confidence: 99%

“…Identification and characterization of such interactions in other colchicine derivatives can be path-breaking 16 . The role of α-T5 loop of colchicine and its derivatives is associated with the better binding energies of their interaction and stabilization with tubulin heterodimer 16 , 17 . Tubulin isotype βIII was identified as a selective site for screening of drug candidates having anti-tumour activity 18 and several colchicine derivatives were evaluated in silico 16 .…”

Section: Resultsmentioning

confidence: 99%

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Docking experiments suggest that gloriosine has microtubule-targeting properties similar to colchicine

Misra

Chaudhary

Singh

et al. 2023

Sci Rep

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Gloriosine, the predominant metabolite of Gloriosa superba L., shares chemical properties with colchicine. We analyze the microtubule-binding affinity of gloriosine at the colchicine binding site (CBS) using an in silico-in vivo approach. The In silico docking of gloriosine showed a binding score of (−) 7.5 kcal/Mol towards β-tubulin at CBS and was validated by overlapping the coupling pose of the docked ligand with co-crystallized colchicine. 2D plots (Ligplot +) showed > 85% overlap between gloriosine and colchicine. The ADMET profile of gloriosine was in accordance with Lipinski’s rule of five. Gloriosine belongs to class II toxicity with anLD50 value of 6 mg/kg. In vivo and transmission electron microscopy studies revealed that gloriosine induces abnormalities in cell division such as condensed chromosomes in C-metaphase and enlarged nucleus with increased nuclear material. Gloriosine treated cells exhibited mitotic index of about 14% compared to control of 24% and high anti-proliferative activity i.e. 63.94% cell viability at a low concentration (0.0004 mg/ml). We conclude that gloriosine has a strong affinity for β-tubulin at CBS and thus can be used as a colchicine alternative in cytology and other clinical conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Docking experiments suggest that gloriosine has microtubule-targeting properties similar to colchicine

Misra

Chaudhary

Singh

et al. 2023

Sci Rep

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“…The stability of the obtained RLD-PI(3)P and RLD-PI(3,4,5)P 3 complexes was investigated through MD simulations. To this purpose, PIPs topologies were built using the General Amber Force Field (GAFF) [ 28 ] and the AM1-BCC charge method [ 29 ] as done previously [ 30 , 31 ]. For each complex, the setup described in section 2.1 was employed to prepare, energy minimize, and equilibrate the system before performing three 200 ns long MD replicas.…”

Section: Methodsmentioning

confidence: 99%

In silico investigation of Alsin RLD conformational dynamics and phosphoinositides binding mechanism

2022

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Alsin is a protein known for its major role in neuronal homeostasis and whose mutation is associated with early-onset neurodegenerative diseases. It has been shown that its relocalization from the cytoplasm to the cell membrane is crucial to induce early endosomes maturation. In particular, evidences suggest that the N-terminal regulator of chromosome condensation 1 like domain (RLD) is necessary for membrane association thanks to its affinity to phosphoinositides, membrane lipids involved in the regulation of several signaling processes. Interestingly, this domain showed affinity towards phosphatidylinositol 3-phosphate [PI(3)P], which is highly expressed in endosomes membrane. However, Alsin structure has not been experimentally resolved yet and molecular mechanisms associated with its biological functions are mostly unknown. In this work, Alsin RLD has been investigated through computational molecular modeling techniques to analyze its conformational dynamics and obtain a representative 3D model of this domain. Moreover, a putative phosphoinositide binding site has been proposed and PI(3)P interaction mechanism studied. Results highlight the substantial conformational stability of Alsin RLD secondary structure and suggest the role of one highly flexible region in the phosphoinositides selectivity of this domain.

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“…Finally, if the complex only lowers β III expression levels rather than eliminating β III altogether, treatment could consist of the complex combined with a drug favoring binding to β III. Several such drugs have been designed to bind to the colchicine site on β III ( Pallante et al, 2020 ); one of these is more effective than paclitaxel on a β III-overexpressing human breast cancer cell line in a transgenic mouse model ( Yeh et al, 2016 ). Similarly, the taxane cabazitaxel is more effective than docetaxel at inhibiting dynamics in vitro of microtubules that contain β III-tubulin than of microtubules that lack β III ( Smiyun et al, 2017 ) and appears to be a useful treatment in advanced prostate cancer ( Wallis et al, 2021 ).…”

Section: Potential Problems and Their Potential Solutionsmentioning

confidence: 99%

Nuclear βII-Tubulin and its Possible Utility in Cancer Diagnosis, Prognosis and Treatment

Ludueña

Walss‐Bass

Portyanko

et al. 2022

Front. Cell Dev. Biol.

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Microtubules are organelles that usually occur only in the cytosol. Walss et al. (1999) discovered the βII isotype of tubulin, complexed with α, in the nuclei of certain cultured cells, in non-microtubule form. When fluorescently labeled tubulins were microinjected into the cells, only αβII appeared in the nucleus, and only after one cycle of nuclear disassembly and reassembly. It appeared as if αβII does not cross the nuclear envelope but is trapped in the nucleus by the re-forming nuclear envelope in whose reassembly βII may be involved. βII is present in the cytoplasm and nuclei of many tumor cells. With some exceptions, normal tissues that expressed βII rarely had βII in their nuclei. It is possible that βII is involved in nuclear reassembly and then disappears from the nucleus. Ruksha et al. (2019) observed that patients whose colon cancer cells in the invasive front showed no βII had a median survival of about 5.5 years, which was more than halved if they had cytosolic βII and further lessened if they had nuclear βII, suggesting that the presence and location of βII in biopsies could be a useful prognostic indicator and also that βII may be involved in cancer progression. Yeh and Ludueña. (2004) observed that many tumors were surrounded by non-cancerous cells exhibiting cytosolic and nuclear βII, suggesting a signaling pathway that causes βII to be synthesized in nearby cells and localized to their nuclei. βII could be useful in cancer diagnosis, since the presence of βII in non-cancerous cells could indicate a nearby tumor. Investigation of this pathway might reveal novel targets for chemotherapy. Another possibility would be to combine αβII with CRISPR-Cas9. This complex would likely enter the nucleus of a cancer cell and, if guided to the appropriate gene, might destroy the cancer cell or make it less aggressive; possible targets will be discussed here. The possibilities raised here about the utility of βII in cancer diagnosis, prognosis, biology and therapy may repay further investigation.

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In silico 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

Cited by 16 publications

References 61 publications

Docking experiments suggest that gloriosine has microtubule-targeting properties similar to colchicine

Docking experiments suggest that gloriosine has microtubule-targeting properties similar to colchicine

In silico investigation of Alsin RLD conformational dynamics and phosphoinositides binding mechanism

Nuclear βII-Tubulin and its Possible Utility in Cancer Diagnosis, Prognosis and Treatment

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