Inhibitors of the Cdc34 acidic loop: A computational investigation integrating molecular dynamics, virtual screening and docking approaches.
Inhibitors of the Cdc34 acidic loop: A computational investigation integrating molecular dynamics, virtual screening and docking approaches.
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Cdc34酸性环的抑制剂：一项计算研究，整合了分子动力学，虚拟筛选和对接方法。
DOI：
10.1016/j.fob.2014.04.011
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发表时间：
2014
期刊：
影响因子：
2.6
通讯作者：
Papaleo, Elena
中科院分区：
文献类型：
--
作者：
Arrigoni, Alberto;Bertini, Luca;De Gioia, Luca;Papaleo, Elena
Cdc 34是一种参与蛋白质泛素化的E2酶，与某些癌症相关。cdc 34活性受磷酸化诱导的酸性环构象变化的调节。我们使用计算方法来识别Cdc 34的潜在抑制化合物。这些抑制剂作为分子铰链将酸环稳定在其非活性的闭合构象中。在参与泛素途径的不同类型的酶中，E2泛素缀合酶在泛素化级联反应中占据中心作用。Cdc 34样E2酶的特征在于在催化位点附近插入12-14个残基，称为酸性环。Cdc 34泛素充电活性受CK 2依赖性磷酸化调节，调节机制涉及酸性环。事实上，磷酸化使环稳定在开放构象中，这是泛素充电的能力。cdc 34与多种疾病有关，如肝细胞癌和前列腺癌。鉴于其作用，发现潜在的抑制性化合物将提供有效调节其活性的手段。在这里，我们进行了计算研究的基础上，分子动力学，虚拟筛选和对接，以确定潜在的抑制化合物Cdc 34，调节酸性环构象。在这项研究中确定的分子已被设计为分子铰链，可以结合酸性环在其封闭的构象，从而抑制Cdc 34介导的泛素化级联在泛素充电步骤。特别是，我们提出了一个药效团模型，具有两个氨基在模型的中心部分和两个侧芳香链，分别建立与酸性环（天冬氨酸108和谷氨酸109）和氢键与丝氨酸139，这是Cdc 34活性的关键残基之一的静电相互作用。
Cdc34 is an E2 enzyme involved in protein ubiquitination and associated with some cancers. Cdc34 activity is modulated by phosphorylation-induced conformational changes of the acidic loop. We used computational approaches to identify potential inhibitory compounds for Cdc34. These inhibitors as molecular hinges stabilizing the acid loop in its inactive, closed conformation. Among the different classes of enzymes involved in the ubiquitin pathway, E2 ubiquitin-conjugating enzymes occupy a central role in the ubiquitination cascade. Cdc34-like E2 enzymes are characterized by a 12–14 residue insertion in the proximity of the catalytic site, known as the acidic loop. Cdc34 ubiquitin-charging activity is regulated by CK2-dependent phosphorylation and the regulatory mechanism involves the acidic loop. Indeed, the phosphorylation stabilizes the loop in an open conformation that is competent for ubiquitin charging. Cdc34 is associated with a variety of diseases, such as hepatocellular carcinomas and prostatic adenocarcinomas. In light of its role, the discovery of potential inhibitory compounds would provide the mean to effectively modulate its activity. Here, we carried out a computational study based on molecular dynamics, virtual screening and docking to identify potential inhibitory compounds of Cdc34, modulating the acidic loop conformation. The molecules identified in this study have been designed to act as molecular hinges that can bind the acidic loop in its closed conformation, thus inhibiting the Cdc34-mediated ubiquitination cascade at the ubiquitin-charging step. In particular, we proposed a pharmacophore model featuring two amino groups in the central part of the model and two lateral aromatic chains, which respectively establish electrostatic interactions with the acidic loop (Asp 108 and Glu 109) and a hydrogen bond with Ser 139, which is one of the key residues for Cdc34 activity.
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影响因子：
2.3
作者：
Lass A;Cocklin R;Scaglione KM;Skowyra M;Korolev S;Goebl M;Skowyra D
通讯作者：
Skowyra D
影响因子：
3.9
作者：
Michelle, Caroline;Vourc'h, Patrick;Mignon, Laurence;Andres, Christian R.
通讯作者：
Andres, Christian R.
E2S：结构上经济和功能上充满。
DOI：
10.1042/bj20100985
发表时间：
2011-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Wenzel DM;Stoll KE;Klevit RE
通讯作者：
Klevit RE
影响因子：
3
作者：
Morris, Garrett M.;Huey, Ruth;Lindstrom, William;Sanner, Michel F.;Belew, Richard K.;Goodsell, David S.;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
影响因子：
5.6
作者：
Irwin JJ;Sterling T;Mysinger MM;Bolstad ES;Coleman RG
通讯作者：
Coleman RG