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Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

[Image: see text] Vinblastine and its derivatives used in clinics as antitumor drugs often cause drug resistance and some serious side effects; thus, it is necessary to study new vinblastine analogues with strong anticancer cytotoxicity and low toxicity. We designed a dimer molecule using two vindol...

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Autores principales: Zhang, Zhengqiong, Lu, Chengqi, Wang, Pei, Li, Aijing, Zhang, Hongbo, Xu, Sichuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682054/
https://www.ncbi.nlm.nih.gov/pubmed/31460305
http://dx.doi.org/10.1021/acsomega.9b00947
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author Zhang, Zhengqiong
Lu, Chengqi
Wang, Pei
Li, Aijing
Zhang, Hongbo
Xu, Sichuan
author_facet Zhang, Zhengqiong
Lu, Chengqi
Wang, Pei
Li, Aijing
Zhang, Hongbo
Xu, Sichuan
author_sort Zhang, Zhengqiong
collection PubMed
description [Image: see text] Vinblastine and its derivatives used in clinics as antitumor drugs often cause drug resistance and some serious side effects; thus, it is necessary to study new vinblastine analogues with strong anticancer cytotoxicity and low toxicity. We designed a dimer molecule using two vindoline-bonded dimer vindoline (DVB) and studied its interaction with α,β-tubulin through the double-sided adhesive mechanism to explore its anticancer cytotoxicity. In our work, DVB was docked into the interface between α-tubulin and β-tubulin to construct a complex protein structure, and then it was simulated for 100 ns using the molecular dynamics technology to become a stable and refined complex protein structure. Based on such a refined structure, the quantum chemistry at the level of the MP2/6-31G(d,p) method was used to calculate the binding energies for DVB interacting with respective residues. By the obtained binding energies, the active site residues for interaction with DVB were found. Up to 20 active sites of residues within α,β-tubulin interacting with DVB are labeled in β-Asp179, β-Glu207, β-Tyr210, β-Asp211, β-Phe214, β-Pro222, β-Tyr224, and β-Leu227 and α-Asn249, α-Arg308, α-Lys326, α-Asn329, α-Ala333, α-Thr334, α-Lys336, α-Lys338, α-Arg339, α-Ser340, α-Thr349, and α-Phe351. The total binding energy between DVB and α,β-tubulin is about −251.0 kJ·mol(–1). The sampling average force potential (PMF) method was further used to study the dissociation free energy (ΔG) along the separation trajectory of α,β-tubulin under the presence of DVB based on the refined structure of DVB with α,β-tubulin. Because of the presence of DVB within the interface between α- and β-tubulin, ΔG is 252.3 kJ·mol(–1). In contrast to the absence of DVB, the separation of pure β-tubulin needs a free energy of 196.9 kJ·mol(–1). The data show that the presence of DVB adds more 55.4 kJ·mol(–1) of ΔG to hinder the normal separation of α,β-tubulin. Compared to vinblastine existing, the free energy required for the separation of α,β-tubulin is 220.5 kJ·mol(–1). Vinblastine and DVB can both be considered through the same double-sided adhesive mechanism to give anticancer cytotoxicity. Because of the presence of DVB, a larger free energy is needed for the separation of α,β-tubulin, which suggests that DVB should have stronger anticancer cytotoxicity than vinblastine and shows that DVB has a broad application prospect.
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spelling pubmed-66820542019-08-27 Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin Zhang, Zhengqiong Lu, Chengqi Wang, Pei Li, Aijing Zhang, Hongbo Xu, Sichuan ACS Omega [Image: see text] Vinblastine and its derivatives used in clinics as antitumor drugs often cause drug resistance and some serious side effects; thus, it is necessary to study new vinblastine analogues with strong anticancer cytotoxicity and low toxicity. We designed a dimer molecule using two vindoline-bonded dimer vindoline (DVB) and studied its interaction with α,β-tubulin through the double-sided adhesive mechanism to explore its anticancer cytotoxicity. In our work, DVB was docked into the interface between α-tubulin and β-tubulin to construct a complex protein structure, and then it was simulated for 100 ns using the molecular dynamics technology to become a stable and refined complex protein structure. Based on such a refined structure, the quantum chemistry at the level of the MP2/6-31G(d,p) method was used to calculate the binding energies for DVB interacting with respective residues. By the obtained binding energies, the active site residues for interaction with DVB were found. Up to 20 active sites of residues within α,β-tubulin interacting with DVB are labeled in β-Asp179, β-Glu207, β-Tyr210, β-Asp211, β-Phe214, β-Pro222, β-Tyr224, and β-Leu227 and α-Asn249, α-Arg308, α-Lys326, α-Asn329, α-Ala333, α-Thr334, α-Lys336, α-Lys338, α-Arg339, α-Ser340, α-Thr349, and α-Phe351. The total binding energy between DVB and α,β-tubulin is about −251.0 kJ·mol(–1). The sampling average force potential (PMF) method was further used to study the dissociation free energy (ΔG) along the separation trajectory of α,β-tubulin under the presence of DVB based on the refined structure of DVB with α,β-tubulin. Because of the presence of DVB within the interface between α- and β-tubulin, ΔG is 252.3 kJ·mol(–1). In contrast to the absence of DVB, the separation of pure β-tubulin needs a free energy of 196.9 kJ·mol(–1). The data show that the presence of DVB adds more 55.4 kJ·mol(–1) of ΔG to hinder the normal separation of α,β-tubulin. Compared to vinblastine existing, the free energy required for the separation of α,β-tubulin is 220.5 kJ·mol(–1). Vinblastine and DVB can both be considered through the same double-sided adhesive mechanism to give anticancer cytotoxicity. Because of the presence of DVB, a larger free energy is needed for the separation of α,β-tubulin, which suggests that DVB should have stronger anticancer cytotoxicity than vinblastine and shows that DVB has a broad application prospect. American Chemical Society 2019-07-10 /pmc/articles/PMC6682054/ /pubmed/31460305 http://dx.doi.org/10.1021/acsomega.9b00947 Text en Copyright © 2019 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Zhang, Zhengqiong
Lu, Chengqi
Wang, Pei
Li, Aijing
Zhang, Hongbo
Xu, Sichuan
Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin
title Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin
title_full Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin
title_fullStr Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin
title_full_unstemmed Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin
title_short Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin
title_sort structural basis and mechanism for vindoline dimers interacting with α,β-tubulin
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682054/
https://www.ncbi.nlm.nih.gov/pubmed/31460305
http://dx.doi.org/10.1021/acsomega.9b00947
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