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发现潜在的RAGE抑制剂,使用基于受体的药解体建模,高通量虚拟查和对接研究

Harbinder Singh¹, Devendra K Agrawal¹

¹Department of Translational Research, College of the Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California USA.

Journal of biotechnology and biomedicine

|December 5, 2023

概括

研究人员使用基于受体的药模型确定了潜在的RAGE抑制剂. 这种方法选了数百万个分子,产生了十种与高级甘氨酸终端产品 (RAGE) 受体结合的化合物,提供了新的治疗途径.

科学领域:

计算化学和药物发现
分子建模和模拟分子模型
药理学和药物化学药理学和药物化学

背景情况:

高级甘氨酸终端产品 (RAGE) 的受体是炎症信号通路中的关键调解器.
愤怒与各种疾病有关,包括心血管,神经退行性疾病,癌症和糖尿病.
抑制RAGE - 配体相互作用是一个有前途的治疗策略.

研究的目的:

发现具有潜在抑制RAGE的结构多样化的小分子.
利用基于受体的药模拟来识别新型RAGE抑制剂.
通过计算来选一个大型化学库的RAGE结合化合物.

主要方法:

使用施罗丁格的阶段开发了RAGE的V-域的两个药模型.
从ChEMBL数据库中选了180万种类似药物的分子.
执行高通量虚拟选,对接和MM-GBSA绑定能量计算.

主要成果:

确定了十个能够结合到RAGE V域上的两个不同的浅结合点的命中分子.
两个化合物,ChEMBL501494和ChEMBL4081874,表现出最有利的结合自由能量.
这些顶级化合物在RAGE结合腔内表现出稳定的受体-连接体复合体形成.

结论:

基于受体的药模拟对于识别潜在的RAGE抑制剂是有效的.
已识别的成功化合物,特别是ChEMBL501494和ChEMBL4081874,是开发RAGE抑制剂的有希望的线索.
这些分子可以作为设计和优化未来RAGE向疗法的基础.

关键词:

在 ChEMBL 数据库中.炎症炎症是一种炎症.在MM-GBSA中使用.制药类型的建模.阶段选阶段选愤怒的抑制剂愤怒的抑制剂虚拟选是一个虚拟的选.

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