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Interaction of microtubule depolymerizing agent indanocine with different human alpha beta tubulin isotypes

Authors
  • KUMBHAR, BV
  • PANDA, D
  • KUNWAR, A
Publication Date
Dec 03, 2018
Identifiers
DOI: 10.1002/2014GL061044
OAI: oai:dsapce.library.iitb.ac.in:100/25070
Source
DSpace at IIT Bombay
Keywords
License
Unknown
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Abstract

Tubulin isotypes are known to regulate the stability and dynamics of microtubules, and are also involved in the development of resistance against microtubule-targeted cancer drugs. Indanocine, a potent microtubule depolymerizing agent, is highly active against multidrug-resistant (MDR) cancer cells without affecting normal cells. It is known to disrupt microtubule dynamics in cells and induce apoptotic cell death. Indanocine is reported to bind to tubulin at the colchicine site i.e. at the interface of alpha beta tubulin heterodimer. However, it's precise binding mode, involved molecular interactions and the binding affinities with different alpha beta-tubulin isotypes present in MDR cells are not well understood. Here, the binding affinities of human alpha beta-tubulin isotypes with indanocine were examined, employing the molecular modeling approach i.e. docking, molecular dynamics simulation and binding energy calculations. Multiple sequence analysis suggests that the amino acid sequences are different in the indanocine binding pockets of beta I,beta IIa, beta III and beta VI isotypes. However, such differences are not observed in the amino acid sequences of beta IVa, beta IVb, and beta V tubulin isotypes at indanocine binding pockets. Docking and molecular dynamics simulation results show that indanocine prefers the interface binding pocket of alpha beta IIa, alpha beta III, alpha beta IVb, alpha beta V, and alpha beta VI tubulin isotypes; whereas it is expelled from the interface binding pocket of alpha beta IVa and alpha beta I-tubulin isotypes. Further, binding free energy calculations show that alpha beta VI has the highest binding affinity and alpha beta I has the lowest binding affinity for indanocine among all beta-tubulin isotypes. The binding free energy decreases in the order of alpha beta VI > alpha beta IVb > alpha beta IIa > alpha beta III > alpha beta V > alpha beta IVa > alpha beta I. Thus, our study provides a significant understanding of involved molecular interactions of indanocine with tubulin isotypes, which may help to design potent indanocine analogues for specific tubulin isotypes in MDR cells in future.

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