Structural analysis for colchicine binding site-targeted ATCAA derivatives as melanoma antagonists

摘要

Melanoma is the fatal form of skin cancer. Herein, a three-dimensional quantitative structure-activity relationship study on a series of 105 colchicine binding site-targeted 2-arylthiazolidine-4-carboxylic acid amides (ATCAA) derivatives as melanoma antagonists was conducted. The optimal CoMSIA model yields a Q2 of 0.556, R2 ncv of 0.833 and R 2 pred of 0.757, while the CoMFA yields a Q2 of 0.569, R2 ncv of 0.812 and R2 pred of 0.589. In addition, molecular docking was also carried out. The study results demonstrated that: (1) Bulky substituents in Rings C and D significantly increase the biological activity of compounds while decrease the activity at Rings A and B; (2) Electropositive groups at Rings A and B as well as electronegative groups at Ring C help to increase the activity; (3) HB donor favors Rings A and D while HB acceptor favors Rings B and C. Besides, a statistical analysis of the key amino acids as well as the ones forming HB with various antagonists of the colchicine binding site was conducted based on 34 essays and found HB to be the key interaction that MTAs have with the colchicine binding site and that Ala 250, Asn 258, Thr 179, Lys 254 and Lys 352 are vital in the composition of the site and the formation of HB. The results of this study provide useful information on designing antagonists with improved activity and insight on the composition of the colchicine binding site.