Computational Prediction of the Mode of Binding of Antitumor Lankacidin C to Tubulin

Lankacidin C, which is an antibiotic
produced by the organism Streptomyces rochei, shows considerable antitumor
activity. The mechanism of its antitumor activity remained elusive
for decades until it was recently shown to overstabilize microtubules
by binding at the taxol binding site of tubulin, causing mitotic arrest
followed by apoptosis. However, the exact binding mode of lankacidin
C inside the tubulin binding pocket remains unknown, an issue that
impedes proper structure-based design, modification, and optimization
of the drug. Here, we have used computational methods to predict the
most likely binding mode of lankacidin C to tubulin. We employed ensemble-based
docking in different software packages, supplemented with molecular
dynamics simulation and subsequent binding-energy prediction. The
molecular dynamics simulations performed on lankacidin C were collectively
1.1 μs long. Also, a multiple-trajectory approach was performed
to assess the stability of different potential binding modes. The
identified binding mode could serve as an ideal starting point for
structural modification and optimization of lankacidin C to enhance
its affinity to the tubulin binding site and therefore improve its
antitumor activity.