Computational repurposing of benzimidazole anthelmintic drugs as potential colchicine binding site inhibitors

Background: Although some benzimidazole-based anthelmintic drugs are found to possess anticancer activity, their modes of binding interactions have not been reported. Methodology: In this study, we aimed to investigate the binding interactions and electronic configurations of nine benzimidazole-based anthelmintics against one of the well-known cancer targets (tubulin protein). Results: Binding affinities of docked benzimidazole drugs into colchicine-binding site were calculated where flubendazole > oxfendazole > nocodazole > mebendazole. Flubendazole was found to bind more efficiently with tubulin protein than other drugs. Quantum mechanics studies revealed that the electron density of HOMO of flubendazole and mebendazole together with their molecular electrostatic potential map are closely similar to that of nocodazole. Conclusion: Our study has ramifications for considering repurposing of flubendazole as a promising anticancer candidate.

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Revisiting Activity of Some Nocodazole Analogues as a Potential Anticancer Drugs Using Molecular Docking and DFT Calculations

Frontiers in Chemistry ◽

10.3389/fchem.2021.628398 ◽

2021 ◽

Vol 9 ◽

Author(s):

Muhammad Khattab ◽

Ahmed A. Al‐Karmalawy

Keyword(s):

Quantum Mechanics ◽

Binding Site ◽

Structural Similarity ◽

Binding Mode ◽

Benzimidazole Derivatives ◽

Binding Affinities ◽

Anticancer Activities ◽

Binding Interactions ◽

Colchicine Binding Site ◽

Tubulin Protein

Although potential anticancer activities of benzimidazole-based anthelmintic drugs have been approved by preclinical and clinical studies, modes of binding interactions have not been reported so far. Therefore, in this study, we aimed to propose binding interactions of some benzimidazole-based anthelmintics with one of the most important cancer targets (Tubulin protein). Studied drugs were selected based on their structural similarity with the cocrystallized ligand (Nocodazole) with tubulin protein. Quantum mechanics calculations were also employed for characterization of electronic configuration of studied drugs at the atomic and molecular level. Order of binding affinities of tested benzimidazole drugs toward colchicine binding site on tubulin protein is as follows: Flubendazole > Oxfendazole > Nocodazole > Mebendazole > Albendazole > Oxibendazole > Fenbendazole > Ciclobendazole > Thiabendazole > Bendazole. By analyzing binding mode and hydrogen bond length between the nine studied benzimidazole drugs and colchicine binding site, Flubendazole was found to bind more efficiently with tubulin protein than other benzimidazole derivatives. The quantum mechanics studies showed that the electron density of HOMO of Flubendazole and Mebendazole together with their MEP map are quite similar to that of Nocodazole which is also consistent with the calculated binding affinities. Our study has ramifications for considering the repurposing of Flubendazole as a promising anticancer candidate.

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Molecular modelling of mebendazole polymorphs as a potential colchicine binding site inhibitor

New Journal of Chemistry ◽

10.1039/d0nj02844d ◽

2020 ◽

Vol 44 (33) ◽

pp. 13990-13996 ◽

Cited By ~ 1

Author(s):

Ahmed A. Al-Karmalawy ◽

Muhammad Khattab

Keyword(s):

Binding Site ◽

Molecular Modelling ◽

Colchicine Binding Site ◽

Tubulin Protein

Form B of mebendazole is the form expected to bind more efficiently with the colchicine binding site within the tubulin protein.

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Synthesis, Anti-proliferative Evaluation, and Molecular Docking Studies of 3-(alkylthio)-5,6-diaryl-1,2,4-triazines as Tubulin Polymerization Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180727114216 ◽

2019 ◽

Vol 16 (11) ◽

pp. 1194-1201 ◽

Cited By ~ 3

Author(s):

Farhad Saravani ◽

Ebrahim Saeedian Moghadam ◽

Hafezeh Salehabadi ◽

Seyednasser Ostad ◽

Morteza Pirali Hamedani ◽

...

Keyword(s):

Molecular Modeling ◽

Cytotoxic Activity ◽

Binding Site ◽

Cell Line ◽

Cell Lines ◽

Tubulin Polymerization ◽

Adenocarcinoma Cell Line ◽

Adenocarcinoma Cell ◽

Colchicine Binding Site ◽

Anti Cancer

Background: The role of microtubules in cell division and signaling, intercellular transport, and mitosis has been well known. Hence, they have been targeted for several anti-cancer drugs. Methods: A series of 3-(alkylthio)-5,6-diphenyl-1,2,4-triazines were prepared and evaluated for their cytotoxic activities in vitro against three human cancer cell lines; human colon carcinoma cells HT-29, human breast adenocarcinoma cell line MCF-7, human Caucasian gastric adenocarcinoma cell line AGS as well as fibroblast cell line NIH-3T3 by MTT assay. Docking simulation was performed to insert these compounds into the crystal structure of tubulin at the colchicine binding site to determine a probable binding model. Compound 5d as the most active compound was selected for studying of microtubule disruption. Results: Compound 5d showed potent cytotoxic activity against all cell lines. The molecular modeling study revealed that some derivatives of triazine strongly bind to colchicine binding site. The tubulin polymerization assay kit showed that the cytotoxic activity of 5d may be related to inhibition of tubulin polymerization. Conclusion: The cytotoxicity and molecular modeling study of the synthesized compounds with their inhibition activity in tubulin polymerization demonstrate the potential of triazine derivatives for development of new anti-cancer agents.

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Synthesis and tubulin interaction of thiocolchicines containing an isothiocyanato group. Synthesis of C(2)-deuterated and C(2)-14C-labeled 7-isothiocyanatodeacetamidothiocolchicine

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19912306 ◽

1991 ◽

Vol 56 (11) ◽

pp. 2306-2312 ◽

Cited By ~ 3

Author(s):

Anjum Muzaffar ◽

Ernest Hamel ◽

Rouli Bai ◽

Arnold Brossi

Keyword(s):

Binding Site ◽

Covalent Bond ◽

Tubulin Polymerization ◽

Low Concentration ◽

Covalent Interaction ◽

Isotope Label ◽

Colchicine Binding Site

Synthesis of isothiocyanato substituted thiocolchicines XI - XIV is described. Introduction of an isotope label is demonstrated with the deuterated isothiocyanate XII and the 14C-labeled analog XIII. These isothiocyanates inhibit tubulin polymerization at low concentration. In addition, the 14C-labeled XIII forms covalent bond(s) with tubulin. Unfortunately, the covalent reaction while rapid, is not inhibited by preincubation of tubulin with colchicine. The covalent interaction of XIII with tubulin thus appears to be nonspecific, limiting its use as a marker of the colchicine binding site on tubulin.

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Binding Interactions of Peptide Aptamers

Molecules ◽

10.3390/molecules25246055 ◽

2020 ◽

Vol 25 (24) ◽

pp. 6055

Author(s):

Roger R. C. New ◽

Tam T. T. Bui ◽

Michal Bogus

Keyword(s):

Amino Acid ◽

Binding Site ◽

Cyclic Peptides ◽

Binding Interactions ◽

Peptide Aptamers ◽

Linear Peptide ◽

Signalling Molecules ◽

Antibody Binding Site ◽

Linear Chains ◽

Protein Receptors

Peptide aptamers are short amino acid chains that are capable of binding specifically to ligands in the same way as their much larger counterparts, antibodies. Ligands of therapeutic interest that can be targeted are other peptide chains or loops located on the surface of protein receptors (e.g., GCPR), which take part in cell-to-cell communications either directly or via the intermediary of hormones or signalling molecules. To confer on aptamers the same sort of conformational rigidity that characterises an antibody binding site, aptamers are often constructed in the form of cyclic peptides, on the assumption that this will encourage stronger binding interactions than would occur if the aptamers were simply linear chains. However, no formal studies have been conducted to confirm the hypothesis that linear peptides will engage in stronger binding interactions with cyclic peptides than with other linear peptides. In this study, the interaction of a model cyclic decamer with a series of linear peptide constructs was compared with that of a linear peptide with the same sequence, showing that the cyclic configuration does confer benefits by increasing the strength of binding.

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