Quantitative Prediction of Multivalent Ligand–Receptor Binding Affinities for Influenza, Cholera, and Anthrax Inhibition,ACS Nano

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Quantitative Prediction of Multivalent Ligand–Receptor Binding Affinities for Influenza, Cholera, and Anthrax Inhibition
ACS Nano ( IF 15.8 ) Pub Date : 2018-02-23 00:00:00 , DOI: 10.1021/acsnano.7b08479
Susanne Liese _{1,

2} , Roland R. Netz ₁

Affiliation

Multivalency achieves strong, yet reversible binding by the simultaneous formation of multiple weak bonds. It is a key interaction principle in biology and promising for the synthesis of high-affinity inhibitors of pathogens. We present a molecular model for the binding affinity of synthetic multivalent ligands onto multivalent receptors consisting of n receptor units arranged on a regular polygon. Ligands consist of a geometrically matching rigid polygonal core to which monovalent ligand units are attached via flexible linker polymers, closely mimicking existing experimental designs. The calculated binding affinities quantitatively agree with experimental studies for cholera toxin (n = 5) and anthrax receptor (n = 7) and allow to predict optimal core size and optimal linker length. Maximal binding affinity is achieved for a core that matches the receptor size and for linkers that have an equilibrium end-to-end distance that is slightly longer than the geometric separation between ligand core and receptor sites. Linkers that are longer than optimal are greatly preferable compared to shorter linkers. The angular steric restriction between ligand unit and linker polymer is shown to be a key parameter. We construct an enhancement diagram that quantifies the multivalent binding affinity compared to monovalent ligands. We conclude that multivalent ligands against influenza viral hemagglutinin (n = 3), cholera toxin (n = 5), and anthrax receptor (n = 7) can outperform monovalent ligands only for a monovalent ligand affinity that exceeds a core-size dependent threshold value. Thus, multivalent drug design needs to balance core size, linker length, as well as monovalent ligand unit affinity.

中文翻译：

流感，霍乱和炭疽抑制的多价配体-受体结合亲和力的定量预测

多价键通过同时形成多个弱键来实现强而可逆的结合。这是生物学中的关键相互作用原理，并有望用于病原体的高亲和力抑制剂的合成。我们提出了一种分子模型，用于合成多价配体对由排列在规则多边形上的n个受体单元组成的多价受体的结合亲和力。配体由几何匹配的刚性多边形核组成，单价配体单元通过柔性接头聚合物连接到该核上，与现有的实验设计极为相似。计算的结合亲和力在数量上与霍乱毒素（n = 5）和炭疽受体（n= 7），并允许预测最佳核心大小和最佳接头长度。对于与受体大小匹配的核心以及平衡端对端距离比配体核心和受体位点之间的几何间隔稍长的连接子，可以实现最大的结合亲和力。与较短的接头相比，长于最佳的接头更可取。配体单元和接头聚合物之间的空间立体角限制是关键参数。我们构建了一个增强图，该图量化了与单价配体相比的多价结合亲和力。我们得出的结论是，针对流感病毒血凝素（n = 3），霍乱毒素（n = 5）和炭疽受体（n= 7）仅在单价配体亲和力超过核心尺寸依赖性阈值的情况下才能胜过单价配体。因此，多价药物设计需要平衡核心大小，接头长度以及单价配体单元亲和力。

更新日期：2018-02-23

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