Bioinspired computational design of lankacidin derivatives for improvement in antitumor activity.

Background: The 17-membered polyketide, lankacidin C, exhibits considerable antitumor activity as a microtubule stabilizer by binding to the paclitaxel binding site. Method: Esterification of the C-7/C-13 hydroxyl in lankacidin C was performed with acetyl, cinnamoyl and hydrocinnamoyl groups and their antitumor activity was assessed to improve the cytotoxicity of lankacidins through bioinspired computational design. Results: Compared with the cytotoxicity of parent lankacidin C against the HeLa cell line, 13-O-cinnamoyl-lankacidin C demonstrated sevenfold higher cytotoxicity. Furthermore, 7,13-di-O-cinnamoyl-lankacidin C exhibited considerable antitumor activity against three tested cell lines. Conclusion: C13-esterification by a cinnamoyl group dramatically improved antitumor activity, in agreement with computational predictions. This finding provides a potential substrate for next-generation lankacidin derivatives with significant antitumor activity.

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.