In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism
| Autor: | Narek Abelyan, Harutyun Sahakyan, Karen Nazaryan, Vahram Arakelov, Grigor Arakelov |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Familial Mediterranean fever Molecular Dynamics Biochemistry chemistry.chemical_compound Computational Chemistry 0302 clinical medicine Tubulin Medicine and Health Sciences Biochemical Simulations Colchicine Amino Acids Free Energy chemistry.chemical_classification Crystallography Multidisciplinary biology Organic Compounds Chemistry Simulation and Modeling Physics Drugs Condensed Matter Physics Amino acid 030220 oncology & carcinogenesis Physical Sciences Crystal Structure Medicine Thermodynamics Research Article Science In silico Single-nucleotide polymorphism Molecular Dynamics Simulation Research and Analysis Methods Polymorphism Single Nucleotide 03 medical and health sciences Tubulins Microtubule medicine Humans Solid State Physics Computer Simulation Gene Pharmacology Organic Chemistry Chemical Compounds Biology and Life Sciences Proteins Computational Biology medicine.disease Cytoskeletal Proteins 030104 developmental biology Amino Acid Substitution biology.protein |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 8, p e0221532 (2019) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0221532 |
| Popis: | Starting from 1972, colchicine is known as the most useful drug for prevention of familial Mediterranean fever attacks. However, some patients do not respond to colchicine treatment, even taken in high doses. Despite the fact, that different hypotheses have been proposed, the molecular mechanisms of colchicine resistance are not completely clear. It is generally known, that colchicine binds β-tubulin and inhibits microtubules polymerization. The β-tubulin gene has SNPs, which lead to amino acid substitutions, and some of them are located in colchicine binding site (CBS). We have assumed, that this SNPs can affect tubulin-colchicine interaction and might be the reason for colchicine resistance. With this in mind, we modeled 7 amino acid substitutions in CBS, performed molecular dynamics simulations of tubulin-colchicine complex and calculated binding energies for every amino acid substitution. Thus, our study shows, that two amino acid substitutions in the β-tubulin, namely A248T and M257V, reduce binding energy for approximately 2-fold. Based on this, we assume, that these amino acid substitutions could be the reason for colchicine resistance. Thus, our study gives a new insight into colchicine resistance mechanism and provides information for designing colchicine alternatives, that could be effective for colchicine resistant patients. |
| Databáze: | OpenAIRE |
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