Arylthioindoles: docking and molecular dynamics studies

Tubulin is considered an important target for anticancer therapy. Paclitaxel and vinca alkaloids are clinically important chemotherapeutic drugs, and are widely used for the treatment of a variety of human tumors. However, restrictions due to toxicity, drug resistance, complex formulations and limited bioavailability highlight the need for novel tubulin inhibitors. Recently, we have reported several arylthioindoles (ATIs) as very effective inhibitors both of tubulin polymerization and of the growth of some carcinoma cell lines.1-3 To investigate the structural basis of the SAR that emerged from the biological results, we carried out docking and molecular dynamics studies. Previously reported ATIs (R1 = COOR)1,2 established one hydrogen bond between the carbonyl group of the ester function and Lys352 and another between the NH group and Thr179 into colchicine site of tubulin. Despite the absence of the ester moiety, binding to beta-tubulin of the new ATIs (R1 = H)3 involved formation of a hydrogen bond between the NH group and Thr179 and positioning of the trimethoxy phenyl group in a hydrophobic pocket close to Cys241. Molecular dynamics simulations confirmed a stable interaction between ATIs and tubulin for both proposed binding modes. Colchine/tubulin complex was also simulated to have a better understanding of its binding mode with tubulin. References (1) De Martino, G.; La Regina, G.; Coluccia, A. et al. J. Med. Chem. 2004, 47, 6120-6123. (2) De Martino, G.; Edler, M. C.; La Regina, G. et al. J. Med. Chem. 2006, 49, 947-954. (3) La Regina, G.; Edler, M. C.; Brancale, A. et al. J. Med. Chem. 2007, ASAP Article.