Effective Screening Strategy Using Ensembled Pharmacophore Models Combined with Cascade Docking: Application to p53-MDM2 Interaction Inhibitors
Effective Screening Strategy Using Ensembled Pharmacophore Models Combined with Cascade Docking: Application to p53-MDM2 Interaction Inhibitors
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使用集成药效团模型结合级联对接的有效筛选策略：在 p53-MDM2 相互作用抑制剂中的应用
DOI：
10.1021/ci400348f
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发表时间：
2013-10
影响因子：
5.6
通讯作者：
You Qi-Dong
中科院分区：
文献类型：
--
作者：
Xue Xin;Wei Jin-Lian;Xu Li-Li;Xi Mei-Yang;Xu Xiao-Li;Liu Fang;Guo Xiao-Ke;Wang Lei;Zhang Xiao-Jin;Zhang Ming-Ye;Lu Meng-Chen;Sun Hao-Peng;You Qi-Dong
蛋白质-蛋白质相互作用（PPI）在细胞功能中起着至关重要的作用，并形成几乎所有生物化学过程的支柱。近年来，蛋白质-蛋白质相互作用抑制剂（PPII）代表了潜在的新药物靶点的宝库。不幸的是，市场上几乎没有成功的PPI药物。基于结构的药效团（SBP）结合对接已被证明是药物开发项目中有用的虚拟筛选（VS）策略。然而，靶点复杂性和结合亲和力预测差的组合阻碍了该策略在PPII发现中的应用。在这里，我们报告了一个有效的VS策略对p53-MDM 2 PPI。首先，我们建立了一个基于p53-MDM 2复合物共晶结构的SBP模型。然后，通过使用基于受体-配体复合物的药效团模型来简化模型，该模型考虑MDM 2与其小分子抑制剂之间的关键结合特征。随后应用级联对接来提高命中率。基于这一策略，我们在NCI和SPECS数据库上进行了VS，并从15个命中中成功发现了6个新化合物，其中化合物1（NSC 5359），K（i）= 180 ± 50 nM。这些化合物可作为先导化合物用于进一步优化。
Protein-protein interactions (PPIs) play a crucial role in cellular function and form the backbone of almost all biochemical processes. In recent years, protein-protein interaction inhibitors (PPIIs) have represented a treasure trove of potential new drug targets. Unfortunately, there are few successful drugs of PPIIs on the market. Structure-based pharmacophore (SBP) combined with docking has been demonstrated as a useful Virtual Screening (VS) strategy in drug development projects. However, the combination of target complexity and poor binding affinity prediction has thwarted the application of this strategy in the discovery of PPIIs. Here we report an effective VS strategy on p53-MDM2 PPI. First, we built a SBP model based on p53-MDM2 complex cocrystal structures. The model was then simplified by using a Receptor-Ligand complex-based pharmacophore model considering the critical binding features between MDM2 and its small molecular inhibitors. Cascade docking was subsequently applied to improve the hit rate. Based on this strategy, we performed VS on NCI and SPECS databases and successfully discovered 6 novel compounds from 15 hits with the best, compound 1 (NSC 5359), K(i) = 180 ± 50 nM. These compounds can serve as lead compounds for further optimization.
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影响因子：
5.6
作者：
Manepalli S;Geffert LM;Surratt CK;Madura JD
通讯作者：
Madura JD
DOI：
10.1007/978-1-62703-236-0_8
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Zhang, Qi;Lu, Hua
通讯作者：
Lu, Hua
影响因子：
5.6
作者：
R. Thilagavathi;R. Mancera
通讯作者：
R. Thilagavathi;R. Mancera
影响因子：
7.3
作者：
Herold, J. Martin;Wigle, Tim J.;Norris, Jacqueline L.;Lam, Robert;Korboukh, Victoria K.;Gao, Cen;Ingerman, Lindsey A.;Kireev, Dmitri B.;Senisterra, Guillermo;Vedadi, Masoud;Tripathy, Ashutosh;Brown, Peter J.;Arrowsmith, Cheryl H.;Jin, Jian;Janzen, William P.;Frye, Stephen V.
通讯作者：
Frye, Stephen V.
影响因子：
3.7
作者：
Verkhivker GM
通讯作者：
Verkhivker GM