Title:Structural Analysis for Colchicine Binding Site-Targeted ATCAA Derivatives as Melanoma Antagonists
VOLUME: 10 ISSUE: 3
Author(s):Jiawei Zhang, Feng Li, Yan Li, Yangyang Guo, Jinghui Wang and Shuwei Zhang
Affiliation:Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian, Liaoning 116023, China.
Keywords:3D-QSAR, colchicine binding site, docking, melanoma cancer antagonists.
Abstract: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
R2
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.
