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通过基于结构的虚拟查发现非硫胺碳酸酶IX抑制剂

Tianheng Cheng^1,2,3, Nihan Wang^1,2,3, Rui Wen^1,2,3

¹Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. mscheng@syphu.edu.cn.

Physical chemistry chemical physics : PCCP

|February 29, 2024

概括

研究人员使用计算方法确定了新的非硫胺碳酸无水酶IX (CA IX) 抑制剂. 这些化合物显示出开发针对CA IX的新抗瘤药物的前景,CA IX是固体瘤中的关键蛋白质.

科学领域:

生物化学生物化学
在瘤学瘤学.
药用化学医学化学

背景情况:

碳酸无水酶IX (CA IX) 在固体瘤中高度表达,使其成为重要的治疗点.
现有的碳酸酶抑制剂 (CAI) 主要是硫胺衍生物,限制了进一步的药物开发.
对于先进的瘤治疗,需要具有独特结构的新型CA IX抑制剂.

研究的目的:

通过基于结构的虚拟查方法发现新的非硫胺碳酸胺酶IX抑制剂.
评估已识别的化合物的抗瘤潜力和药理特性.
探索针对CA IX表达瘤的新疗法策略.

主要方法:

对FDA药物数据库的基于结构的虚拟选.
在体外酶分析测试以确定对CA IX的抑制活性.
分子动力学模拟和结合的自由能量计算.
药理性质和安全性评估的ADME/毒素预测.

主要成果:

确定了三种非硫胺化合物:3-pyridinemethanol,procodazole和帕米德罗尼酸具有CA IX抑制活性.
3-皮里迪尼甲醇,普罗科达和帕米德罗尼酸的IC50值分别为0.42微米,8.35微米和8.51微米.
计算分析证实了有利的结合稳定性,相互作用模式,并预测了良好的ADME/毒素概况.

结论:

通过计算策略成功发现和验证了三种新的非硫胺CA IX抑制剂.
这些化合物代表了开发下一代抗癌疗法的有希望的候选人.
这些发现支持使用计算方法来识别瘤学新药候选药物.

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