Identifying novel molecular structures for advanced melanoma by ligand-based virtual screening.
Identifying novel molecular structures for advanced melanoma by ligand-based virtual screening.
复制标题
DOI：
10.1021/ci800445a
复制
发表时间：
2009-06
影响因子：
5.6
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Wang Z;Lu Y;Seibel W;Miller DD;Li W
我们最近发现了一类新的噻唑类似物，它们对黑色素瘤细胞非常有效。为了扩展构效关系研究并探索潜在的新分子支架，我们对包含342，910个小分子的化合物文库进行了广泛的基于配体的虚拟筛选。使用我们的先导分子的结构进行了两种不同的虚拟筛选方法：1）使用来自Accelerys的Scitegic Pipeline Pilot的基于连接性的搜索和2）使用Schrodinger软件的分子形状相似性搜索。使用测试化合物库，这两种方法可以将相似化合物排名非常高，将不相似化合物排名非常低，从而验证我们的筛选方法。对从这些搜索中识别出的结构进行了分析，并对选定的化合物进行了体外测试，以评估它们对黑色素瘤癌细胞系的活性。一些分子显示出良好的抗癌活性。虽然没有一种鉴定出的化合物显示出比我们的先导化合物更好的活性，但它们为我们的先导化合物的结构修饰提供了重要的见解，并提供了新的平台，我们可以在其上优化新的抗癌化合物。基于这种虚拟筛选的新合成的类似物之一具有改善的针对黑素瘤的效力和选择性。
We recently discovered a new class of thiazole analogs that are highly potent against melanoma cells. To expand the structure-activity relationship study and to explore potential new molecular scaffolds, we performed extensive ligand-based virtual screening against a compound library containing 342,910 small molecules. Two different approaches of virtual screening were carried out using the structure of our lead molecule: 1) connectivity-based search using Scitegic Pipeline Pilot from Accelerys and 2) molecular shape similarity search using Schrodinger software. Using a testing compound library, both approaches can rank similar compounds very high and rank dissimilar compounds very low, thus validating our screening methods. Structures identified from these searches were analyzed, and selected compounds were tested in vitro to assess their activity against melanoma cancer cell lines. Several molecules showed good anticancer activity. While none of the identified compounds showed better activity than our lead compound, they provided important insight into structural modifications for our lead compound and also provided novel platforms on which we can optimize new classes of anticancer compounds. One of the newly synthesized analogs based on this virtual screening has improved potency and selectivity against melanoma.
登录
查看更多内容
影响因子：
7.3
作者：
Lu Y;Li CM;Wang Z;Ross CR 2nd;Chen J;Dalton JT;Li W;Miller DD
通讯作者：
Miller DD
影响因子：
2.2
作者：
Shellman, YG;Ribble, D;Dellavalle, RP
通讯作者：
Dellavalle, RP
影响因子：
45.3
作者：
Chapman, PB;Einhorn, LH;Kirkwood, JM
通讯作者：
Kirkwood, JM
影响因子：
254.7
作者：
Jemal, A;Tiwari, RC;Thun, MJ
通讯作者：
Thun, MJ
影响因子：
45.3
作者：
Kaufmann, R;Spieth, K;Dummer, R
通讯作者：
Dummer, R