Theoretical insight into the structural mechanism for the binding of vinblastine with tubulin
| Autor: | Sichuan Xu, Shaoming Chi, Jiwei Zhang, Wei Xie |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Vincristine
Protein Folding Vinca medicine.medical_treatment Molecular Sequence Data Static Electricity Drug resistance Pharmacology Molecular Dynamics Simulation Vinblastine Protein Structure Secondary Structural Biology Tubulin Catalytic Domain medicine Humans Amino Acid Sequence Cytotoxicity Molecular Biology Vinca Alkaloids Chemotherapy biology Chemistry Hydrogen Bonding General Medicine biology.organism_classification Tubulin Modulators Protein Structure Tertiary Molecular Docking Simulation Protein Subunits Cancer cell biology.protein Thermodynamics medicine.drug Protein Binding |
| Zdroj: | Journal of biomolecular structuredynamics. 33(10) |
| ISSN: | 1538-0254 |
| Popis: | Vinblastine (VLB) is one of vinca alkaloids with high cytotoxicity toward cancer cells approved for clinical use. However, because of drug resistance, toxicity, and other side effects caused from the use of VLB, new vinca alkaloids with higher cytotoxicity toward cancer cells and other good qualities need to develop. One strategy is to further study and better understand the essence why VLB possesses the high cytotoxicity toward cancer cells. In present work, by using molecular simulation, molecular docking, density functional calculation, and the crystal structure of α,β-tubulin complex, we find two modes labeled in catharanthine moiety (CM) and vindoline moiety (VM) modes of VLB bound with the interface of α,β-tubulin to probe the essence why VLB has the high cytotoxicity toward cancer cells. In the CM mode, nine key residues B-Ser178, B-Asp179, B-Glu183, B-Tyr210, B-Asp226, C-Lys326, C-Asp327, C-Lys336, and C-Lys352 from the α,β-tubulin complex are determined as the active sites for the interaction of VLB with α,β-tubulin. Some of them such as B-Ser178, B-Glu183, B-Tyr210, B-Asp226, C-Lys326, C-Asp327, and C-Lys336 are newly identified as the active sites in present work. The affinity between VLB and the active pocket within the interface of α,β-tubulin is -60.8 kJ mol(-1) in the CM mode. In the VM mode, that is a new mode established in present paper, nine similar key residues B-Lys176, B-Ser178, B-Asp179, B-Glu183, B-Tyr210, B-Asp226, C-Lys326, C-Asp327, and C-Lys336 from the α,β-tubulin complex are found as the active sites for the interaction with VLB. The difference is from one key residue C-Lys352 in the CM mode changed to the key residue B-Lys176 in the VM mode. The affinity between VLB and the active pocket within the interface of α,β-tubulin is -96.3 kJ mol(-1) in the VM mode. Based on the results obtained in present work, and because VLB looks like two faces, composed of CM and VM both to have similar polar active groups, to interact with the active sites, we suggest double-faces sticking mechanism for the binding of VLB to the interface of α,β-tubulin. The double-faces sticking mechanism can be used to qualitatively explain high cytotoxicity toward cancer cells of vinca alkaloids including vinblastine, vincristine, vindestine, and vinorelbine approved for clinical use and vinflunine still in a phase III clinical trial. Furthermore, this mechanism will be applied to develop novel vinca alkaloids with much higher cytotoxicity toward cancer cells. |
| Databáze: | OpenAIRE |
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