Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform.
Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform.
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DOI：
10.1093/nar/gkn1043
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发表时间：
2009-03
影响因子：
14.9
通讯作者：
Trent JO
中科院分区：
文献类型：
--
作者：
Holt PA;Ragazzon P;Strekowski L;Chaires JB;Trent JO
虚拟筛选是发现具有潜在药用价值的新小分子的一种越来越有吸引力的方法。我们介绍了一种新的策略，集成使用的分子对接软件Surflex的竞争透析的方法与实验验证。这种整合的方法用于鉴定选择性结合三链体DNA poly（dA）-[poly（dT）]2的配体。实际上筛选了含有1200万个配体的文库，以鉴定与已知的三链体嵌入剂萘基喹啉MHQ-12具有化学和结构相似性的化合物。使用具有高结构相似性的化合物的进一步分子对接研究产生了两种化合物，然后通过竞争透析证明这两种化合物对三链体核酸具有比MHQ-12更上级的亲和力和选择性。其中一种化合物具有与MHQ-12不同的化学骨架，这证明了这种策略能够“支架跳跃”并识别具有新结合特性的小分子。通过圆二色性和热变性研究这些化合物的生物物理特性证实了它们的结合模式和选择性。这些研究为我们的综合筛选策略提供了原理证明，并表明该平台可以扩展到发现靶向治疗相关核酸形态的新化合物。
Virtual Screening is an increasingly attractive way to discover new small molecules with potential medicinal value. We introduce a novel strategy that integrates use of the molecular docking software Surflex with experimental validation by the method of competition dialysis. This integrated approach was used to identify ligands that selectively bind to the triplex DNA poly(dA)-[poly(dT)]2. A library containing ∼2 million ligands was virtually screened to identify compounds with chemical and structural similarity to a known triplex intercalator, the napthylquinoline MHQ-12. Further molecular docking studies using compounds with high structural similarity resulted in two compounds that were then demonstrated by competition dialysis to have a superior affinity and selectivity for the triplex nucleic acid than MHQ-12. One of the compounds has a different chemical backbone than MHQ-12, which demonstrates the ability of this strategy to ‘scaffold hop’ and to identify small molecules with novel binding properties. Biophysical characterization of these compounds by circular dichroism and thermal denaturation studies confirmed their binding mode and selectivity. These studies provide a proof-of-principle for our integrated screening strategy, and suggest that this platform may be extended to discover new compounds that target therapeutically relevant nucleic acid morphologies.
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影响因子：
3.9
作者：
Chaires, Jonathan B.
通讯作者：
Chaires, Jonathan B.
DOI：
10.2174/1568011054222292
发表时间：
2005-07-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
Chaires, Jonathan B.
通讯作者：
Chaires, Jonathan B.
影响因子：
7.3
作者：
Cleves, Ann E.;Jain, Ajay N.
通讯作者：
Jain, Ajay N.
影响因子：
15
作者：
Chaires, JB;Ren, JS;Strekowski, L
通讯作者：
Strekowski, L
影响因子：
15
作者：
Arya, DP;Xue, L;Tennant, P
通讯作者：
Tennant, P