Double-sides sticking mechanism of vinblastine interacting with α,β-tubulin to get activity against cancer cells

Zhou, Xiaowen; Xu, Zeren; Li, Aijing; Zhang, Zhengqiong; Xu, Shihong

doi:10.1080/07391102.2018.1539412

Cited by 26 publications

(20 citation statements)

References 68 publications

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“…The crucial target for this group of drugs is tubulin. These drugs can bind to tubulin and interfere with the microtubule dynamics of tubulin [58].…”

Section: Tubulin Binding Activitymentioning

confidence: 99%

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Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

et al. 2020

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Combretastatins are a class of closely related stilbenes (combretastatins A), dihydrostilbenes (combretastatins B), phenanthrenes (combretastatins C) and macrocyclic lactones (combretastatins D) found in the bark of Combretum caffrum (Eckl. & Zeyh.) Kuntze, commonly known as the South African bush willow. Some of the compounds in this series have been shown to be among the most potent antitubulin agents known. Due to their structural simplicity many analogs have also been synthesized. Combretastatin A4 phosphate is the most frequently tested compounds in preclinical and clinical trials. It is a water-soluble prodrug that the body can rapidly metabolize to combretastatin A4, which exhibits anti-tumor properties. In addition, in vitro and in vivo studies on combretastatins have determined that these compounds also have antioxidant, anti-inflammatory and antimicrobial effects. Nano-based formulations of natural or synthetic active agents such as combretastatin A4 phosphate exhibit several clear advantages, including improved low water solubility, prolonged circulation, drug targeting properties, enhanced efficiency, as well as fewer side effects. In this review, a synopsis of the recent literature exploring the combretastatins, their potential effects and nanoformulations as lead compounds in clinical applications is provided.

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“…The crucial target for this group of drugs is tubulin. These drugs can bind to tubulin and interfere with the microtubule dynamics of tubulin [58].…”

Section: Tubulin Binding Activitymentioning

confidence: 99%

“…These protofilaments constitute the cylindrical and helical microtubule wall [59,60]. Microtubules have various important functions in eukaryotic cells such as cell division (the formation of the mitotic spindle), cell motility and migration, intracellular transport, cell signaling and maintaining cell polarity [58,59,61].…”

Section: Tubulin Binding Activitymentioning

confidence: 99%

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

et al. 2020

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“…The free energy of pure α,β-tubulin separation was reported. 18 However, for the sake of better understanding in comparison to the presence of DVB, we briefly introduce the free energy for pure α,β-tubulin moving along its separation trajectory.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Compared with vinblastine, the free energy required for the separation of α,β-tubulin is going up 220.5 kJ·mol –1 . 18 Vinblastine and DVB can be considered to acquire anticancer cytotoxicity using the same double-sided adhesive mechanism. In the presence of DVB, larger free energy for the separation of α,β-tubulin is required, which suggests that DVB would possess a stronger anticancer cytotoxicity than vinblastine, thus theoretically to imply that DVB has a broad application and a clear development prospect.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Wang

et al. 2019

ACS Omega

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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 (Δ G ) 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, Δ G 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 Δ G 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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“…These biological activities are driven by intricate molecular interactions between the indole agent and its corresponding therapeutic target that controls disease. [1,8,[12][13][14][15][16][17][18] The inventory of clinically used or promising indole-based compounds includes as tructural spectrum of broad chemical diversity,f rom structurally simple synthetic indoles (e.g.,o ndansetron) to indole alkaloids composed of complex,f used ring systems that are elaborated into some of the most impressivem olecular architectures found in nature (e.g.,v inblastine).…”

Section: Introductionmentioning

confidence: 99%

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

Norwood

Huigens

2019

ChemBioChem

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Indole‐containing compounds demonstrate an array of biological activities relevant to numerous human diseases. The biological activities of diverse indole‐based agents are driven by molecular interactions between indole agent and critical therapeutic target. The chemical inventory of medicinally useful or promising indole compounds spans the entire structural spectrum, from simple synthetic indoles to highly complex indole alkaloids. In an analogous fashion, the chemistry behind the indole heterocycle is unique and provides rich opportunities for extensive synthetic chemistry, enabling the construction and development of novel indole compounds to explore chemical space. This review will present heterocyclic chemistry of the indole nucleus, indole compounds of clinical use, complex indole alkaloids and indole‐inspired discovery efforts by multiple research groups interested in using novel indole‐containing small molecules to drive discoveries in human biology and medicine.

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Double-sides sticking mechanism of vinblastine interacting with α,β-tubulin to get activity against cancer cells

Cited by 26 publications

References 68 publications

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

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

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

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