基于药效团的虚拟筛选的新型策略在腺苷脱氨酶抑制剂检测和体外研究中的应用。
A new strategy based on pharmacophore-based virtual screening in adenosine deaminase inhibitors detection and in-vitro study.
机构信息
Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.
出版信息
Daru. 2012 Oct 22;20(1):64. doi: 10.1186/2008-2231-20-64.
BACKGROUND AND THE PURPOSE OF THE STUDY
Adenosine deaminase (ADA) inhibition not only may be applied for the treatment of ischemic injury, hypertension, lymphomas and leukaemia, but also they have been considered as anti- inflammatory drugs. On the other hand according to literatures, ADA inhibitors without a nucleoside framework would improve pharmacokinetics and decrease toxicity. Hence we have carried out a rational pharmacophore design for non-nucleoside inhibitors filtration.
METHODS
A merged pharmacophore model based on the most potent non-nucleoside inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and natural products were generated and applied for compounds filtration. The effects of filtrated compounds based on pharmacophore and docking studies investigated on ADA by UV and Fluorescence spectroscopy techniques.
RESULTS
Extracted compounds were find efficiently inhibit ADA, and the most potent (2) shows an inhibition constant equal to 20 μM. Besides, Fluorescence spectroscopy studies revealed that enzyme 3D structure bear further change in lower concentrations of compound 2.
CONCLUSION
3 non-nucleoside inhibitors for ADA are presented. According to obtained results from UV and fluorescence spectroscopy, such interesting pharmacophore template with multiple approaches will help us to extract or design compound with desired properties.
背景与研究目的
腺苷脱氨酶 (ADA) 抑制剂不仅可用于治疗缺血性损伤、高血压、淋巴瘤和白血病，还被认为是抗炎药物。另一方面，根据文献记载，没有核苷骨架的 ADA 抑制剂可以改善药代动力学并降低毒性。因此，我们进行了基于最有效的非核苷抑制剂赤式-9-(2-羟基-3-壬基)腺嘌呤 (EHNA) 和天然产物的合理药效团设计，以筛选非核苷抑制剂。
方法
基于最有效的非核苷抑制剂赤式-9-(2-羟基-3-壬基)腺嘌呤 (EHNA) 和天然产物生成了一个合并的药效团模型，并将其应用于化合物筛选。通过紫外和荧光光谱技术研究了基于药效团和对接研究筛选出的化合物对 ADA 的影响。
结果
提取的化合物有效地抑制了 ADA，其中最有效的化合物 (2) 的抑制常数等于 20 μM。此外，荧光光谱研究表明，在较低浓度的化合物 2 下，酶的 3D 结构发生了进一步的变化。
结论
提出了 3 种 ADA 的非核苷抑制剂。根据紫外和荧光光谱获得的结果，这种具有多种方法的有趣药效团模板将有助于我们提取或设计具有所需特性的化合物。
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