When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?
When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?
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DOI：
10.1021/acs.jmedchem.6b00725
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发表时间：
2017-01-12
影响因子：
7.3
通讯作者：
Karanicolas, John
中科院分区：
文献类型：
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作者：
Malhotra, Shipra;Karanicolas, John
传统的命中-引导优化假设在化学结构的阐述时，配体相对于受体保持其结合模式。在这里，我们建立了一个大规模的收集相关的配体对解决复杂的相同的蛋白质合作伙伴：我们发现，41的297对（14%），结合模式的变化后，制定的较小的配体。虽然某些配体的物理化学性质易导致结合模式的变化，特别是那些定义片段的性质，但简单的基于结构的建模证明对于识别改变结合模式的取代更有效。一些配体对改变结合模式，因为添加的取代基将与原始姿势的受体发生不可调和的冲突，而另一些配体对改变结合模式，因为添加的取代基能够实现新的、更强的相互作用，这些相互作用仅在不同的姿势中可用。可以使用替代姿势接合其靶标的支架可以使得能够沿着沿着多个发散途径进行生产性的基于结构的优化。
Traditional hit-to-lead optimization assumes that upon elaboration of chemical structure, the ligand retains its binding, mode relative to the receptor. Here, we build a large-scale collection of related ligand pairs solved in complex with the same protein partner: we find that for 41 of 297 pairs (14%), the binding mode changes upon elaboration of the smaller ligand. While certain ligand physiochemical properties predispose changes in binding mode, particularly those properties that define fragments, simple structure-based modeling proves far more effective for identifying substitutions that alter the binding mode. Some ligand pairs change binding mode because the added substituent would irreconcilably conflict with the receptor in the original pose, whereas others change because the added substituent enables new, stronger interactions that are available only in a different pose. Scaffolds that can engage their target using alternate poses may enable productive structure-based optimization along multiple divergent pathways.