Higher-Affinity Agonists of 5-HT1AR Discovered through Tuning the Binding-Site Flexibility
Higher-Affinity Agonists of 5-HT1AR Discovered through Tuning the Binding-Site Flexibility
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通过调节结合位点灵活性发现更高亲和力的 5-HT1AR 激动剂
DOI：
10.1021/acs.jcim.5b00164
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发表时间：
2015-08-01
影响因子：
5.6
通讯作者：
Fu, Wei
中科院分区：
文献类型：
--
作者：
Lian, Peng;Li, LinLang;Fu, Wei
高亲和力和高选择性的5-HT 1AR激动剂的发现已成为非常有吸引力的，因为它们对多种5-HT 1AR相关的心理和神经问题具有潜在的治疗作用。基于我们先前设计的先导化合物FW 01（Ki = 51.9 nM，在本研究中表示为9a），我们对5-HT 1AR-9a结合进行了大规模的分子动力学模拟和分子对接操作。我们发现9a的头基发生了翻转包装事件，并且我们还发现其尾基可以灵活地结合在5-HT 1AR的激动剂结合位点上。通过对9a头基的翻转堆积现象和9a尾基的结合灵活性的微调，我们通过分子对接操作和第一性原理计算，虚拟设计了一系列新的9a衍生物，并预测这些新设计的9a衍生物应该是更高亲和力的5-HT 1AR激动剂。新的9a衍生物的计算预测已经证实了我们的湿实验研究，化学合成，结合亲和力测定，和激动功能测定。我们的计算设计和湿实验测量之间的一致性导致我们发现了5-HT 1AR的更高亲和力的激动剂，受体结合亲和力增加了1050倍，激动功能提高了1025倍。此外，我们新设计的5-HT 1AR激动剂对5-HT 1AR的选择性高于5-HT 2AR亚型，也高于三种多巴胺受体亚型（D1、D2和D3）。
Discovery of high-affinity and high-selectivity agonists of 5-HT1AR has become very attractive due to their potential therapeutic effects on multiple 5-HT1AR-related psychological and neurological problems. On the basis of our previously designed lead compound FW01 (Ki = 51.9 nM, denoted as 9a in the present study), we performed large-scale molecular dynamics simulations and molecular docking operations on 5-HT1AR-9a binding. We found the flip-packing events for the headgroup of 9a, and we also found that its tail group could bind flexibly at the agonist-binding site of 5-HT1AR. By finely tuning the flip-packing phenomenon of the 9a headgroup and tuning the binding flexibility of 9a tail group, we virtually designed a series of new 9a derivatives through molecular docking operations and first-principles calculations and predicted that these newly designed 9a derivatives should be higher-affinity agonists of 5-HT1AR. The computational predictions on the new 9a derivatives have been confirmed by our wet-experimental studies as chemical synthesis, binding affinity assays, and agonistic-function assays. The consistency between our computational design and wet-experimental measurements has led to our discovery of higher-affinity agonists of 5-HT1AR, with ∼50-fold increase in receptor-binding affinity and ∼25-fold improvements in agonistic function. In addition, our newly designed 5-HT1AR agonists showed very high selectivity of 5-HT1AR over subtype 5-HT2AR and also over three subtypes of dopamine receptors (D1, D2, and D3).