Identification of ligand binding sites in intrinsically disordered proteins with a differential binding score.
Identification of ligand binding sites in intrinsically disordered proteins with a differential binding score.
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DOI：
10.1038/s41598-021-00869-4
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发表时间：
2021-11-19
影响因子：
4.6
通讯作者：
Krishnan VV
中科院分区：
文献类型：
--
作者：
Chen QH;Krishnan VV
筛选直接与本质无序蛋白质 (IDP) 整体结合的配体以发现新药的潜在命中或先导化合物是一个新兴但具有挑战性的领域，因为 IDP 缺乏明确且有序的 3D 蛋白质结构。为了探索新的基于 IDP 的合理药物发现策略，定义了差异结合评分 (DIBS)。 DIBS 的基础是定量确定配体对 IDP 指定的构象集合的结合偏好与对同一蛋白质的随机卷曲构象集合的结合偏好。对构象的重复采样进行整体对接程序，并测试统计显着性的结果确定 IDP 的优先配体结合位点。这种方法的结果准确再现了最近文献中关于配体表没食子儿茶素没食子酸酯 (EGCG) 与肿瘤抑制因子 p53 本质上无序的 N 末端结构域结合的实验数据。结合现有的方法来开发一种针对 IDP 筛选配体的新方法，作为基于 IDP 的药物发现的筛选工具可能很有价值。
Screening ligands directly binding to an ensemble of intrinsically disordered proteins (IDP) to discover potential hits or leads for new drugs is an emerging but challenging area as IDPs lack well-defined and ordered 3D-protein structures. To explore a new IDP-based rational drug discovery strategy, a differential binding score (DIBS) is defined. The basis of DIBS is to quantitatively determine the binding preference of a ligand to an ensemble of conformations specified by IDP versus such preferences to an ensemble of random coil conformations of the same protein. Ensemble docking procedures performed on repeated sampling of conformations, and the results tested for statistical significance determine the preferential ligand binding sites of the IDP. The results of this approach closely reproduce the experimental data from recent literature on the binding of the ligand epigallocatechin gallate (EGCG) to the intrinsically disordered N-terminal domain of the tumor suppressor p53. Combining established approaches in developing a new method to screen ligands against IDPs could be valuable as a screening tool for IDP-based drug discovery.
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影响因子：
3.7
作者：
Wilkop TE;Wang M;Heringer A;Singh J;Zakharov F;Krishnan VV;Drakakaki G
通讯作者：
Drakakaki G
影响因子：
2.9
作者：
Carlson, HA;Masukawa, KM;McCammon, JA
通讯作者：
McCammon, JA
影响因子：
13.8
作者：
Csermely, Peter;Palotai, Robin;Nussinov, Ruth
通讯作者：
Nussinov, Ruth
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：
14.8
作者：
Forli S;Huey R;Pique ME;Sanner MF;Goodsell DS;Olson AJ
通讯作者：
Olson AJ