In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism.
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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0221532 |
| _version_ | 1819144762204094464 |
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| author | Harutyun Sahakyan Narek Abelyan Vahram Arakelov Grigor Arakelov Karen Nazaryan |
| author_facet | Harutyun Sahakyan Narek Abelyan Vahram Arakelov Grigor Arakelov Karen Nazaryan |
| author_sort | Harutyun Sahakyan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T12:47:17Z |
| format | Article |
| id | doaj.art-28a891bfefcc4c14b828922a1362eb72 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T12:47:17Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-28a891bfefcc4c14b828922a1362eb722022-12-21T18:25:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01148e022153210.1371/journal.pone.0221532In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism.Harutyun SahakyanNarek AbelyanVahram ArakelovGrigor ArakelovKaren NazaryanStarting 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.https://doi.org/10.1371/journal.pone.0221532 |
| spellingShingle | Harutyun Sahakyan Narek Abelyan Vahram Arakelov Grigor Arakelov Karen Nazaryan In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism. PLoS ONE |
| title | In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism. |
| title_full | In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism. |
| title_fullStr | In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism. |
| title_full_unstemmed | In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism. |
| title_short | In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism. |
| title_sort | in silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism |
| url | https://doi.org/10.1371/journal.pone.0221532 |
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