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 αβ tubulin heterodimer. However, it’s precise binding mode, involved molecular interactions and the binding affinities with different αβ-tubulin isotypes present in MDR cells are not well understood. Here, the binding affinities of human αβ-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 βI, βIIa, βIII and βVI isotypes. However, such differences are not observed in the amino acid sequences of βIVa, βIVb, and βV tubulin isotypes at indanocine binding pockets. Docking and molecular dynamics simulation results show that indanocine prefers the interface binding pocket of αβIIa, αβIII, αβIVb, αβV, and αβVI tubulin isotypes; whereas it is expelled from the interface binding pocket of αβIVa and αβI-tubulin isotypes. Further, binding free energy calculations show that αβVI has the highest binding affinity and αβI has the lowest binding affinity for indanocine among all β-tubulin isotypes. The binding free energy decreases in the order of αβVI > αβIVb > αβIIa > αβIII > αβV > αβIVa > αβI. 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.
Highlights
Microtubules are dynamic cytoskeleton filamentous proteins; they play essential roles in cell division, cell movement, and intracellular transport [1]
We built homology models of these seven human αβ-tubulin isotypes and performed molecular docking of indanocine and molecular dynamics simulations of αβ tubulin-indanocine complexes to explore the effect of residue composition on the binding interaction of indanocine
The residue compositions were found to be different at the indanocine binding pocket of human βI, βIIa, βIII and βVI tubulin isotypes, whereas no such differences were found in the βIVa, βIVb and βV tubulin isotypes
Summary
Microtubules are dynamic cytoskeleton filamentous proteins; they play essential roles in cell division, cell movement, and intracellular transport [1]. These α/β-tubulin are encoded by multiple genes which are expressed tissue-. Had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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