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Do crystal structures obviate the need for theoretical models of GPCRs for structure based virtual screening

机译：Crystal Structures是否需要基于结构的虚拟筛选的GPCR理论模型

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Recent highly expected structural characterizations of agonist-bound and antagonist-bound beta-2 adrenoreceptor (β2AR) by X-ray crystallography have been widely regarded as critical advances to enable more effective structure-based discovery of GPCRs ligands. It appears that this very important development may have undermined many previous efforts to develop 3D theoretical models of GPCRs. To address this question directly we have compared several historical β2AR models versus the inactive state and nanobody-stabilized active state of β2AR crystal structures in terms of their structural similarity and effectiveness of use in virtual screening for β2AR specific agonists and antagonists. Theoretical models, incluing both homology and de novo types, were collected from five different groups who have published extensively in the field of GPCRs modeling; all models were built before X-ray structures became available. In general, β2AR theoretical models differ significantly from the crystal structure in terms of TMH definition and the global packing. Nevertheless, surprisingly, several models afforded hit rates resulting from virtual screening of large chemical library enriched by known β2AR ligands that exceeded those using X-ray structures; the hit rates were particularly higher for agonists. Furthemore, the screening performance of models is associated with local structural quality such as the RMSDs for binding pocket residues and the ability to capture accurately most if not all critical protein/ligand interactions. These results suggest that carefully built models of GPCRs could capture critical chemical and structural features of the binding pocket thus may be even more useful for practical structure-based drug discovery than X-ray structures.
机译：X射线晶体学通过X射线晶体学的激动剂结合和拮抗剂结合的β-2肾上腺素（β2AR）的高度预期的结构表征已被广泛地被视为关键进展，以实现更有效的GPCRS配体的基于组织的发现。看来这一非常重要的发展可能会破坏许多以前开发GPCR的3D理论模型的努力。为了直接解决这个问题，我们已经比较了几种历史β2AR模型与β2AR晶体结构的非活性状态和纳米体稳定的主动状态，其结构相似性和在虚拟筛选中使用的β2AR特异性激动剂和拮抗剂的有效性方面。从GPCRS造型领域发布的五种不同的群体中收集了含有同源性和De Novo类​​型的理论模型;在X射线结构可用之前，所有型号都建成。通常，在TMH定义和全球包装方面，β2AR理论模型与晶体结构显着不同。然而，令人惊讶的是，几种模型得到了由富含使用X射线结构的已知β2AR配体的大型化学物质的虚拟筛选产生的次数，得到了富集的大型化学文科;激动剂的命中率特别高。 Furthemore，模型的筛选性能与局部结构质量相关的诸如RMSDS用于结合袋残基的RMSD，如果不是所有关键蛋白质/配体相互作用，则精确地捕获最佳。这些结果表明，GPCR的仔细构建模型可以捕获束缚口袋的临界化学和结构特征，因此对于比X射线结构的实际结构的药物发现更有用。

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