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

[Image: see text] 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.