Structural insights into targeting of the colchicine binding site by ELR510444 and parbendazole to achieve rational drug design

Lei, Jiahong; Ma, Lingling; Jinghong, Xian; Chen, Hai; Zhou, Jianjian; Chen, Hao; Lei, Qian; Li, Yuyan; Wang, Yanyan; Wang, Yuxi

doi:10.1039/d1ra01173a

Cited by 3 publications

(4 citation statements)

References 28 publications

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“…25,26 Many studies have shown that colchicine destabilises microtubules in the cytoskeletal structures. 6,10,34,35 Cell morphology images confirmed that colchicine changed the cytoskeletal structures, proving that colchicine could inhibit microtubule polymerisation at the nanoscale. Colchicine has been shown to be a depressant in cancer treatment.…”

Section: Biomechanical Properties Of Cells Have Been Identifiedmentioning

confidence: 84%

“…Cell mechanics and disease states are influenced by changes in cytoskeletal architecture induced by chemotherapy regimens and anticancer drugs 25,26 . Many studies have shown that colchicine destabilises microtubules in the cytoskeletal structures 6,10,34,35 . Cell morphology images confirmed that colchicine changed the cytoskeletal structures, proving that colchicine could inhibit microtubule polymerisation at the nanoscale.…”

Section: Discussionmentioning

confidence: 98%

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Mechanism of action and side effects of colchicine based on biomechanical properties of cells

Liu

Chen

Gao

et al. 2023

Journal of Microscopy

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Many diseases are related to changes in the biomechanical properties of cells; their study can provide a theoretical basis for drug screening and can explain the internal working of living cells. In this study, the biomechanical properties of nephrocytes (VERO cells), hepatocytes (HL‐7702 cells), and hepatoma cells (SMCC‐7721 cells) in culture were detected by atomic force microscopy (AFM) to analyse the side effects of colchicine at different concentrations (0.1 μg/mL (A) and 0.2 μg/mL (B)) at the nanoscale for 2, 4 and 6 h. Compared with the corresponding control cells, the damage to the treated cells increased in a dose‐dependent manner. Among normal cells, the injury of nephrocytes (VERO cells) was markedly worse than that of hepatocytes (HL‐7702 cells) in both colchicine solutions A and B. Based on the analyses of biomechanical properties, the colchicine solution reduced the rate of division and inhibited metastasis of SMCC‐7721 cells. By comparing these two concentrations, we found that the anticancer effect of colchicine solution A was greater than that of solution B. Studying the mechanical properties of biological cells can help understand the mechanism of drug action at the molecular level and provide a theoretical basis for preventing the emergence and diagnosis of diseases at the nanoscale.

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Section: Biomechanical Properties Of Cells Have Been Identifiedmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Mechanism of action and side effects of colchicine based on biomechanical properties of cells

Liu

Chen

Gao

et al. 2023

Journal of Microscopy

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“…Among recently reported colchicine-binding site inhibitors are dihydroquinoxalinone 6a (SB226) [ 41 ], pyrrolopyrimidine 6b [ 42 ] and sulfonamides 7a and 7b [ 43 , 44 ]. Interestingly 5 , 6a , 6b , 7a and 7b , together with the recently reported quinazoline 6c [ 45 ], lack the characteristic 3,4,5-trimethoxyaryl pharmacophore.…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative and Tubulin-Destabilising Effects of 3-(Prop-1-en-2-yl)azetidin-2-Ones and Related Compounds in MCF-7 and MDA-MB-231 Breast Cancer Cells

et al. 2023

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A series of novel 3-(prop-1-en-2-yl)azetidin-2-one, 3-allylazetidin-2-one and 3-(buta-1,3-dien-1-yl)azetidin-2-one analogues of combretastatin A-4 (CA-4) were designed and synthesised as colchicine-binding site inhibitors (CBSI) in which the ethylene bridge of CA-4 was replaced with a β-lactam (2-azetidinone) scaffold. These compounds, together with related prodrugs, were evaluated for their antiproliferative activity, cell cycle effects and ability to inhibit tubulin assembly. The compounds demonstrated significant in vitro antiproliferative activities in MCF-7 breast cancer cells, particularly for compounds 9h, 9q, 9r, 10p, 10r and 11h, with IC50 values in the range 10–33 nM. These compounds were also potent in the triple-negative breast cancer (TBNC) cell line MDA-MB-231, with IC50 values in the range 23–33 nM, and were comparable with the activity of CA-4. The compounds inhibited the polymerisation of tubulin in vitro, with significant reduction in tubulin polymerization, and were shown to interact at the colchicine-binding site on tubulin. Flow cytometry demonstrated that compound 9q arrested MCF-7 cells in the G2/M phase and resulted in cellular apoptosis. The antimitotic properties of 9q in MCF-7 human breast cancer cells were also evaluated, and the effect on the organization of microtubules in the cells after treatment with compound 9q was observed using confocal microscopy. The immunofluorescence results confirm that β-lactam 9q is targeting tubulin and resulted in mitotic catastrophe in MCF-7 cells. In silico molecular docking supports the hypothesis that the compounds interact with the colchicine-binding domain of tubulin. Compound 9q is a novel potent microtubule-destabilising agent with potential as a promising lead compound for the development of new antitumour agents.

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“…The first interaction zone comprises the COL pocket, whereas the second zone is populated by chemical entities that connect the two aforementioned sites. The proximity between these sites has recently led to the rational design of compounds that could occupy the benzimidazole and COL sites in order to enhance their anticancer activity . Moreover, the benzimidazole site exhibits significant variations in the amino acid composition among some target and off-target β-tubulin isotypes. − In an earlier study, our research group found that the substitution of Glu with Ala at position 198 in the β-tubulin isotype VI (βVI, TUBB1 gene) diminishes the binding affinity of CBZ derivatives to this off-target tubulin, which is normally expressed in blood leukocytes and bone marrow. , …”

Section: Introductionmentioning

confidence: 99%

Structure-Based Optimization of Carbendazim-Derived Tubulin Polymerization Inhibitors through Alchemical Free Energy Calculations

Cano-González,

Espinosa-Mendoza,

Matadamas-Martínez

et al. 2023

J. Chem. Inf. Model.

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Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis in human cancer cells by inhibiting tubulin polymerization. Crystallographic structures of α/β-tubulin multimers complexed with nocodazole and mebendazole, two carbendazim derivatives with potent anticancer activity, highlighted the possibility of designing compounds that occupy both benzimidazole- and colchicine-binding sites. In addition, previous studies have demonstrated that the incorporation of a phenoxy group at position 5/6 of carbendazim increases the antiproliferative activity in cancer cell lines. Despite the significant progress made in identifying new tubulin-targeting anticancer compounds, further modifications are needed to enhance their potency and safety. In this study, we explored the impact of modifying the phenoxy substitution pattern on antiproliferative activity. Alchemical free energy calculations were used to predict the binding free energy difference upon ligand modification and define the most viable path for structure optimization. Based on these calculations, seven compounds were synthesized and evaluated against lung and colon cancer cell lines. Our results showed that compound 5a, which incorporates an α-naphthyloxy substitution, exhibits the highest antiproliferative activity against both cancer lines (SK-LU-1 and SW620, IC50 < 100 nM) and induces morphological changes in the cells associated with mitotic arrest and mitotic catastrophe. Nevertheless, the tubulin polymerization assay showed that 5a has a lower inhibitory potency than nocodazole. Molecular dynamics simulations suggested that this low antitubulin activity could be associated with the loss of the key H-bond interaction with V236. This study provides insights into the design of novel carbendazim derivatives with anticancer activity.

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Structural insights into targeting of the colchicine binding site by ELR510444 and parbendazole to achieve rational drug design

Abstract: Crystal structures of tubulin complexed with ELR510444 and parbendazole facilitate the design of novel colchicine binding site inhibitors.

Cited by 3 publications

References 28 publications

Mechanism of action and side effects of colchicine based on biomechanical properties of cells

Mechanism of action and side effects of colchicine based on biomechanical properties of cells

Antiproliferative and Tubulin-Destabilising Effects of 3-(Prop-1-en-2-yl)azetidin-2-Ones and Related Compounds in MCF-7 and MDA-MB-231 Breast Cancer Cells

Structure-Based Optimization of Carbendazim-Derived Tubulin Polymerization Inhibitors through Alchemical Free Energy Calculations

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