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发现新的IDO1/TDO2双抑制剂:一个共识虚拟选方法与分子动力学模拟,并结合自由能量分析

Naufa Hanif^1,2, Suat Sari¹

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.

Journal of biomolecular structure & dynamics

|March 18, 2024

概括

这项研究使用虚拟查确定了里胺2,3-二氧化酶1 (IDO1) 和二二氧化酶2 (TDO2) 的新型双抑制剂. 这些化合物通过克服免疫逃避,显示出作为癌症免疫治疗药物的前景.

科学领域:

生物化学和药理学生物化学和药理学
计算化学计算化学
在瘤学瘤学.

背景情况:

癌细胞通过过度表达胺2,3-二氧化酶1 (IDO1) 和二二氧化酶2 (TDO2) 来逃避免疫反应.
向IDO1和TDO2是癌症免疫疗法的策略,但双重抑制剂很少,只有三种达到人体试验.
现有的IDO1抑制剂具有局限性,需要寻找新的双作用剂.

研究的目的:

通过基于结构的虚拟查 (SBVS) 识别IDO1和TDO2的新型双抑制剂.
评估潜在的候选药物,以获得有利的药理动力学特性和安全性.
为进一步开发提供化合物,作为当前癌症免疫疗法的辅助剂.

主要方法:

在ZINC15自然产品库中使用基于共识结构的虚拟选 (SBVS).
使用两个不同的软件程序将选定的化合物对接到holo IDO1和TDO2.
进行的形评估包括药理动力学,毒性,CYP3A4亲和力,分子动力学 (MD) 模拟和MM-GBSA结合自由能量计算.

主要成果:

根据高共识对接得分和关键酶相互作用,确定了五种潜在的 IDO1/TDO2 双重抑制剂 (10-14 化合物).
顶级化合物表现出有利的药理动力学,预测毒性低,并且没有显著的CYP3A4结合.
MD模拟和MM-GBSA分析证实了对化合物10和11的强烈结合亲和力.

结论:

已识别的虚拟命中代表了新型IDO1/TDO2双抑制剂在癌症治疗中的有希望的候选人.
这些化合物显示出双重抑制的潜力,有利的安全性和药理动力学特征.
需要进一步的体外和体内验证,以确认这些化合物的临床前潜力作为全体IDO1/TDO2双抑制剂.

关键词:

它是Holo IDO1/TDO2双抑制剂.模拟MDMD的模拟 MM-GBSA具有约束力的自由能源分析.癌症免疫疗法免疫疗法达成共识虚拟查虚拟查

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