Rational Design of α-Conotoxin RegIIA Analogues Selectively Inhibiting the Human α3β2 Nicotinic Acetylcholine Receptor through Computational Scanning.,ACS Chemical Neuroscience

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Rational Design of α-Conotoxin RegIIA Analogues Selectively Inhibiting the Human α3β2 Nicotinic Acetylcholine Receptor through Computational Scanning.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-07-10 , DOI: 10.1021/acschemneuro.0c00293
Qingliang Xu ₁ , Han-Shen Tae ₂ , Zihao Wang ₁ , Tao Jiang _{1,

3} , David J Adams ₂ , Rilei Yu _{1,

3}

Affiliation

Engineering the selectivity of α-conotoxins for nicotinic acetylcholine receptors (nAChRs) presents considerable complexity and challenges, as it involves the optimization of their binding affinities to multiple highly conserved nAChR subtypes. Here, we applied a computational-based scanning approach for the rational design of α-conotoxin RegIIA analogues selectively targeting the human (h) α3β2 versus hα3β4 nAChRs. Binding mode analyses suggested that several residues in loop II of RegIIA (position 9, 10, and 11) formed nonconserved interactions with residues of the β2 and β4 subunits. The molecular mechanics generalized Born surface area method was applied for in silico sequence scanning of RegIIA position 9, 10, and 11 on frames extracted from single molecular dynamics simulation trajectory. RegIIA analogues with favorable predicted binding affinities solely to the hα3β2 nAChR were synthesized and tested electrophysiologically. We report three RegIIA analogues, with position 9 aromatic residue substitutions, exhibiting a 10- to 37-fold subtype selectivity improvement for hα3β2 compared to hα3β4 nAChR. The in silico scanning method proposed from this study has considerable potential for the efficient design of nAChR subtype selective antagonists in the future.

中文翻译：

通过计算扫描选择性抑制人α3β2烟碱乙酰胆碱受体的α-芋螺毒素RegIIA类似物的合理设计。

设计α-芋螺毒素对烟碱乙酰胆碱受体（nAChRs）的选择性提出了相当大的复杂性和挑战，因为这涉及优化它们与多种高度保守的nAChR亚型的结合亲和力。在这里，我们应用了基于计算的扫描方法来合理设计α-芋螺毒素RegIIA类似物，使其有针对性地靶向人（h）α3β2和hα3β4nAChRs。结合模式分析表明，RegIIA的环II（位置9、10和11）中的几个残基与β2和β4亚基的残基形成非保守相互作用。分子力学广义Born表面积法在计算机上的应用从单分子动力学模拟轨迹提取的帧上RegIIA位置9、10和11的序列扫描。合成了仅对hα3β2nAChR具有有利的预测结合亲和力的RegIIA类似物，并进行了电生理学测试。我们报告了三个RegIIA类似物，具有9位芳香族残基取代，与hα3β4nAChR相比，对hα3β2的选择性提高了10到37倍。将在硅片从这项研究中提出的扫描方法对nAChR子在未来的选择性拮抗剂的有效设计相当大的潜力。

更新日期：2020-09-16

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