结构稳定性引导的脚手架跳跃和针对结直肠癌的坦基拉酶抑制剂的计算建模
1Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, Najran, Saudi Arabia.
PloS one
|September 19, 2025
概括
这项研究使用计算方法确定了用于结直肠癌 (CRC) 治疗的新型坦基拉酶抑制剂. 化合物138594346和138594428作为针对性CRC治疗的潜在候选药物具有前景.
科学领域:
- 计算化学计算化学
- 药物发现 药物发现 药物发现
- 在瘤学瘤学.
背景情况:
- 结肠直肠癌 (CRC) 是全球癌症死亡的主要原因.
- 异常的Wnt/β-catenin信号传递,通常是由于APC突变,驱动CRC的进展.
- 坦基拉酶是这种途径的关键调节者,也是潜在的治疗标.
研究的目的:
- 发现用于结直肠癌 (CRC) 治疗的新型坦基拉酶抑制剂.
- 采用全面的计算方法来识别有前途的候选药物.
- 通过计算来评估已识别的化合物的稳定性和抑制潜力.
主要方法:
- 使用参考抑制剂 (RK-582) 对坦基拉酶晶体结构进行基于基的查.
- 虚拟选PubChem化合物,然后进行药物相似性过.
- 密度函数理论 (DFT) 计算,分子对接和500 ns分子动力学 (MD) 模拟.
- 在已知的坦基拉酶抑制剂上训练的机器学习模型来预测活性 (pIC50).
主要成果:
- 三种化合物 (PubChem CID: 138594346,138594730,138594428) 被选择进行进一步分析.
- DFT计算表明,化合物138594428的电子稳定性很高,而138594346.6的稳定性/反应性平衡.
- MD模拟证实了蛋白质-连接体复合体的结构稳定性,其中138594346显示了最低的波动.
- 机器学习模型预测化合物138594346 (7.70) 和138594428 (7.41) 的高pIC50值,与参考值 (7.71) 相比.
结论:
- 化合物138594346和138594428显示出作为坦基拉酶抑制剂的显著潜力.
- 这些化合物需要进一步的实验验证,以便开发向的CRC治疗方法.
- 计算方法在识别癌症治疗的新药候选药物方面是有效的.
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