The Recognition of Unrelated Ligands by Identical Proteins,ACS Chemical Biology

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The Recognition of Unrelated Ligands by Identical Proteins
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-08-10 00:00:00 , DOI: 10.1021/acschembio.8b00443
Joshua Pottel ₁ , Anat Levit ₁ , Magdalena Korczynska ₁ , Marcus Fischer ₂ , Brian K. Shoichet ₁

Affiliation

Unrelated ligands, often found in drug discovery campaigns, can bind to the same receptor, even with the same protein residues. To investigate how this might occur, and whether it might be typically possible to find unrelated ligands for the same drug target, we sought examples of topologically unrelated ligands that bound to the same protein in the same site. Seventy-six pairs of ligands, each bound to the same protein (152 complexes total), were considered, classified into three groups. In the first (31 pairs of complexes), unrelated ligands interacted largely with the same pocket residues through different functional groups. In the second group (39 pairs), the unrelated ligand in each pair engaged different residues, though still within the same pocket. The smallest group (6 pairs) contained ligands with different scaffolds but with shared functional groups interacting with the same residues. We found that there are multiple chemically unrelated but physically similar functional groups that can complement any given local protein pocket; when these functional group substitutions are combined within a single molecule, they lead to topologically unrelated ligands that can each well-complement a site. It may be that many active and orthosteric sites can recognize topologically unrelated ligands.

中文翻译：

相同蛋白质对无关配体的识别

在药物开发活动中经常发现的不相关配体，即使具有相同的蛋白质残基，也可以与相同的受体结合。为了研究这种情况如何发生以及通常是否有可能为同一药物靶标找到不相关的配体，我们寻找了在相同位点结合相同蛋白质的拓扑无关的配体的实例。考虑了七十六对配体，每对配体都结合到相同的蛋白质上（共152个复合物），分为三组。在第一个（31对复合物）中，不相关的配体通过不同的官能团与相同的口袋残基很大程度上相互作用。在第二组（39对）中，尽管仍然在同一口袋中，但每对中无关的配体都具有不同的残基。最小的一组（6对）包含具有不同支架的配体，但具有与相同残基相互作用的共享官能团。我们发现，存在多个化学上不相关但物理上相似的官能团，可以与任何给定的局部蛋白质袋互补。当这些官能团取代合并在一个分子中时，它们会导致拓扑上不相关的配体，每个配体都能很好地互补一个位点。可能是许多活性位点和正构位点都可以识别与拓扑无关的配体。它们会导致拓扑上不相关的配体，每个配体都能很好地互补一个位点。可能是许多活性位点和正构位点都可以识别与拓扑无关的配体。它们会导致拓扑上不相关的配体，每个配体都能很好地互补一个位点。可能是许多活性位点和正构位点都可以识别与拓扑无关的配体。

更新日期：2018-08-10

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