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论文类型：期刊论文

发表时间：2014-05-01

发表刊物：MEDICINAL CHEMISTRY

收录刊物：SCIE、PubMed、Scopus

卷号：10

期号：3

页面范围：277-286

ISSN号：1573-4064

关键字：3D-QSAR; colchicine binding site; docking; melanoma cancer 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 Q(2) of 0.556, R-ncv(2) of 0.833 and R-2 pred of 0.757, while the CoMFA yields a Q(2) of 0.569, R-ncv(2) of 0.812 and R-2 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.