The TwistDock workflow for evaluation of bivalent Smac mimetics targeting XIAP
The TwistDock workflow for evaluation of bivalent Smac mimetics targeting XIAP
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用于评估针对 XIAP 的二价 Smac 模拟物的 TwistDock 工作流程
DOI：
10.2147/dddt.s194276
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Feng Shengzhong
中科院分区：
文献类型：
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作者：
Huang Qingsheng;Peng Yin;Peng Yuefeng;Wei Dan;Wei Yanjie;Feng Shengzhong
目的：基于XIAP的天然抑制剂Smac的模拟物是用于治疗癌症的有希望的候选药物。二价Smac模拟物以比单价模拟物更高的效力抑制XIAP，但是如何优化连接两个单价结合基序的接头仍然存在争议。研究方法：为了构建用于评估各种接头的二价复合物结构的集合，我们在本文中提出了一个名为TwistDock的工作流程，该工作流程由单价对接和接头扭转的步骤组成，其中对自由度进行采样，重点关注接头的单键的旋转。结果如下：所得到的二价复合物的构象在构象空间中相对于由连接基序引入的两个反应坐标随机分布，这两个反应坐标是两个结合基序的距离和通过连接基序和每个结合基序的两个平面的二面角。从10种焓值最低的构象出发的分子动力学研究表明，结合亲和力最大的化合物之一化合物9所参与的复合物的构象变化趋势与其他化合物不同。通过对该复合体的伞形采样，我们发现了其自由能景观的全局最小值。结构表明，接头有利于紧凑的构象，并且XIAP的两个BIR结构域在相对侧包围配体。结论：TwistDock可用于靶向XIAP及类似受体二聚化或寡聚化的双价配体的微调。
Purpose: Mimetics based on Smac, the native inhibitor of XIAP, are promising drug-candidates for the treatment of cancer. Bivalent Smac mimetics inhibit XIAP with even higher potency than monovalent mimetics, but how to optimize the linker that tethers the two monovalent binding motifs remains controversial. Methods: To construct an ensemble of bivalent complex structures for evaluating various linkers, we propose herein a workflow, named TwistDock, consisting of steps of monovalent docking and linker twisting, in which the degrees of freedom are sampled focusing on the rotation of single bonds of the linker. Results: The obtained conformations of bivalent complex distribute randomly in the conformational space with respect to two reaction coordinates introduced by the linker, which are the distance of the two binding motifs and the dihedral angle of the two planes through the linker and each of the binding motifs. Molecular dynamics starting from 10 conformations with the lowest enthalpy of every complex shows that the conformational tendency of the complex participated by compound 9, one of the compounds with the largest binding affinity, is distinct from others. By umbrella sampling of the complex, we find its global minimum of the free energy landscape. The structure shows that the linker favors a compact conformation, and the two BIR domains of XIAP encompass the ligand on the opposite sides. Conclusion: TwistDock can be used in fine-tuning of bivalent ligands targeting XIAP and similar receptors dimerized or oligomerized.