In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Computer Simulation*; Colchicine/*pharmacology ; Tubulin/*chemistry; Amino Acid Substitution ; Humans ; Molecular Dynamics Simulation ; Polymorphism, Single Nucleotide/genetics ; Thermodynamics ; Tubulin/genetics

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.
Competing Interests: The authors have declared that no competing interests exist.

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0 (Tubulin)
SML2Y3J35T (Colchicine)

Date Created: 20190824 Date Completed: 20200303 Latest Revision: 20200303

20240105

PMC6707608

10.1371/journal.pone.0221532

31442266