A molecular modeling study of inhibitors of nuclear factor kappa-B (p50) - DNA binding
A molecular modeling study of inhibitors of nuclear factor kappa-B (p50) - DNA binding
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DOI：
10.1023/b:jcam.0000021835.72265.63
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发表时间：
2003-12-01
影响因子：
3.5
通讯作者：
Ramos, MJ
中科院分区：
文献类型：
--
作者：
Pande, V;Sharma, RK;Ramos, MJ
核因子-kappaB(NF-kappaB)是REL家族的一种可诱导转录因子，被IkappaB家族蛋白隔离在细胞质中。核因子-kappaB可以以多种二聚体形式存在，但p50/p65异源二聚体是主要形式。包括病毒产物在内的一系列刺激和氧化应激激活了NF-kappaB，导致IkappaB的磷酸化和蛋白酶体依赖的降解，导致游离的NF-kappaB的释放。这个游离的核因子-kappaB然后结合到它的目标位点(DNA中的kappaB位点)来启动转录。这些kappaB位点也存在于HIV-1的长末端重复序列(LTR)中，因此，NF-kappaB(p50亚基)与LTR-DNA的结合在病毒复制中是至关重要的。在这方面，靶向直接结合p50-DNA是设计抗HIV基因表达抑制剂的一种新方法，它不存在与其他抗HIV策略不同的耐药性问题。本研究是我们寻找特异性抑制p50-DNA结合的线索的一部分。我们一直在实验研究不同类型的这些抑制剂，在这项工作中，我们试图对它们与p50-DNA结合的结构机制得到一个共同的定义。使用三类不同的抑制剂，我们模拟了它们与NF-kappaB的p50亚单位的DNA结合区(DBR)的关联。对接研究是使用基于遗传算法的程序(GOLD)进行的。此外，为了比较缓蚀剂与DBR之间的静电互补性，为DBR和每个缓蚀剂产生了分子静电势(MEP)。对接结果表明，每个活性缓蚀剂都有很强的氢键相互作用网络，而活性较低的缓蚀剂则相反。此外，MEPS显示，p50的DBR代表正电电位表面，而活性缓蚀剂代表互补的电负性表面。通过目前的模拟研究，我们得出结论，针对p50-DNA结合的新导线所具有的主要性质应该是具有与p50的DBR形成强大的氢键网络的能力，并且最好在其外围表面具有电负电位。
Nuclear Factor-kappa B (NF-kappaB) is an inducible transcription factor of the Rel family, and is sequestered in the cytoplasm by the IkappaB family of proteins. NF-kappaB can exist in several dimeric forms, but the p50/p65 heterodimer is the predominant one. Activation of NF-kappaB by a range of stimuli including viral products, and oxidative stress, leads to phosphorylation and proteasome dependent degradation of IkappaB, leading to the release of free NF-kappaB. This free NF-kappaB then binds to its target sites (kappaB sites in the DNA) to initiate transcription. These kappaB sites are also present in the Long Terminal Repeat (LTR) of HIV-1, and hence NF-kappaB (p50 subunit) binding to LTR-DNA is critical in viral replication. Targeting direct p50-DNA binding, in this regard, is a novel approach to design anti-HIV gene expression inhibitors, which do not have the problem of resistance unlike in other anti-HIV strategies. The present study is a part of our search for leads for the specific inhibition of p50-DNA binding. We have been experimentally studying different types of these inhibitors, and in this work, we attempted to get a common definition of their structural mechanism onto p50-DNA binding. Using three different classes of inhibitors, we modelled their association with the DNA-Binding Region (DBR) of the p50 subunit of NF-kappaB. Docking studies were carried out using a genetic algorithm based program (GOLD). Further, to compare electrostatic complementarity in the association of the inhibitors with the DBR, Molecular Electrostatic Potentials (MEPs) were generated for the DBR and each inhibitor. The results of docking revealed a strong network of hydrogen bonding interactions for every active inhibitor, and the contrary for the less active ones. Further, the MEPs revealed that the DBR of p50 represents a surface of electropositive potential, and the active inhibitors represent a complementary electronegative surface. With the present modelling study we conclude that the principal properties to be possessed by the new leads against p50-DNA binding should be that of having the ability to make a strong network of hydrogen bonds with the DBR of p50, and preferably, having electronegative potentials in their peripheral surface.