From Virtual to Real Screening for D3 Dopamine Receptor Ligands
From Virtual to Real Screening for D3 Dopamine Receptor Ligands
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D3 多巴胺受体配体从虚拟筛选到真实筛选
DOI：
10.1002/cbic.200400400
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发表时间：
2005
期刊：
影响因子：
3.2
通讯作者：
G. Schneider
中科院分区：
文献类型：
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作者：
Evgeny Byvatov;B. Sasse;H. Stark;G. Schneider
多巴胺能系统的不平衡涉及各种神经和神经精神障碍，例如帕金森病、精神分裂症和药物滥用。一种多巴胺受体亚型的选择性吸引可能代表一种改进的治疗方法，或者至少是一种评估该亚型在疾病中的（病理）生理功能的好方法。在这里，我们专注于多巴胺D3受体，因为这种亚型在几种疾病中起着重要的神经调节作用，并在中枢神经系统中具有独特的定位。由于D3受体显示出与D2受体的高序列同一性，因此交叉反应性对于所使用的大多数化合物是一个问题。虽然这一领域的研究已经进行了几十年，许多铅结构具有不令人满意的选择性。由于许多描述的化合物具有不同的结构元素表现出一些D3受体的偏好，我们专注于这些元素，首先通过虚拟，然后通过真实的筛选最有前途的化合物，以找到新的领导候选人进一步优化。从Specs（2003年6月发布的229685种化合物，Specs，德尔夫特，荷兰）和Interbioscreen（IBS; 2004年2月发布的25601种化合物，Interbioscreen，莫斯科，俄罗斯）的集合中虚拟筛选的合成化合物被研究为多巴胺D3受体的潜在选择性配体。我们使用BP 897（1）的类似物进行了筛选，BP 897（1）是一种D3受体偏好性部分激动剂
Imbalance of the dopaminergic system is involved in various neurological and neuropsychiatric disorders, for example, Parkinson’s disease, schizophrenia, and drug abuse. Selective attraction of one dopamine receptor subtype could represent an improved therapeutic approach or at least a good way to evaluate the (patho)physiological functions of this subtype in the disorder. Here we focused on the dopamine D3 receptor, since this subtype plays an important neuroregulatory role in several diseases and possesses a distinct localization in the central nervous system. As D3 receptors display high sequence identity to D2 receptors, cross-reactivity is a problem for most compounds used. Although this field of research has been worked on for decades, many lead structures have unsatisfying selectivity. Since numerous described compounds with diverse structural elements showed some D3 receptor preference, we focused on these elements—first by virtual and then by real screening of the most promising compounds—to find new lead candidates for further optimization. Virtually screened synthetic compounds from collections of Specs (229 685 compounds from release June 2003, Specs, Delft, The Netherlands) and Interbioscreen (IBS; 25 601 compounds from release February 2004, Interbioscreen, Moscow, Russia) were investigated as potentially selective ligands at dopamine D3 receptors. We performed this screening by using analogues of BP897 (1), a D3 receptor-preferring partial agonist