通过虚拟查识别除了黄素之外的增强型循环氧化酶-2 (COX-2) 抑制剂,以准与炎症相关的代谢并发症

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¹Non-Communicable Disease Research Unit, South African Medical Research Council, Tygerberg 7505, South Africa.

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概括

这项研究确定了新型的黄素类化合物作为潜在的循环氧化酶-2 (COX-2) 抑制剂. 这些候选药物显示出治疗炎症相关疾病的前景,克服了黄素.

科学领域:

药用化学医学化学
计算机化药物发现技术
药理学药理学是指药理学的学科.

背景情况:

循环氧化酶-2 (COX-2) 是炎症通路中的关键酶,也是炎症相关疾病的治疗点.
黄素是一种天然的多,通过COX-2抑制表现出抗炎性质,但具有较差的溶解性和生物可用性.
为了有效的治疗应用,开发具有改进药物样性质的库尔库明类比是必不可少的.

研究的目的:

使用in silico方法识别具有增强药物特性的新型库尔库类支架作为潜在的COX-2抑制剂.
评估已识别的化合物的结合亲和力,药物相似性和安全性.

主要方法:

基于库尔库明的关键结合部分的药模型被用于ZINC-22数据库的虚拟选.
通过分子对接,利宾斯基的五项规则,毒性预测和P-糖蛋白/细胞染色体P450相互作用分析来优先考虑打击.
进行了分子动力学模拟和结合能计算,以评估复杂的稳定性和结合强度.

主要成果:

虚拟选产生了237个候选化合物,通过分子对接优先选择了10个顶级结合剂.
化合物ZINC32605424和ZINC47133707显示出与利宾斯基规则的偏差;ZINC47133693和ZINC09499196显示出有利的安全概况.
ZINC32605424表现出最强的COX-2结合亲和力,由范德瓦尔斯力稳定,在Tyr323和Leu320具有关键相互作用.

结论:

一些与黄素类似的化合物,包括ZINC32605424,ZINC08644750,ZINC47133693和ZINC09499196,表现出强大的COX-2抑制作用.
这些已识别的化合物在治疗与炎症相关的代谢并发症方面具有重要的临床前验证潜力.
在 silico 方法成功地确定了具有改善治疗潜力的有前途的 COX-2 抑制剂.

关键词:

库尔库明是一种黄素.循环氧基因酶-2 的作用.分子对接的分子对接.分子动态模拟的分子动态模拟.制药器模型的制药模型.

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