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使用计算机辅助药物设计方法,设计新型的小分子,从印林-2-one中衍生而成,作为强大的TRKs抑制剂

Rachid Haloui¹, Khaoula Mkhayar¹, Ossama Daoui¹

¹Laboratory of Engineering, Systems, and Applications, National School of Applied Sciences, Sidi Mohamed Ben Abdellah-Fez University, Fez, Morocco.

Journal of biomolecular structure & dynamics

|January 13, 2024

概括

新的印丁-2-衍生物显示出对热氨酸受体激酶 (TRK) 酶的强烈抑制,为抗癌药物提供了有前途的候选药物. 计算建模和选确定了T1,T3和T4的化合物,以便进一步开发.

科学领域:

药用化学医学化学
计算机化药物设计技术
在瘤学瘤学.

背景情况:

热氨酸受体激酶 (TRKs) 是由基因融合驱动的癌症的关键标.
印度二衍生物已经显示出显著的TRK抑制活性.
优化这些分子对于开发有效的抗癌疗法至关重要.

研究的目的:

设计具有增强TRK抑制活性和有利的药理动力学特征的新型印二衍生物.
用3D-QSAR方法来进行结构-活动关系分析和分子设计.
为了确定TRK驱动癌症的有前途的候选药物.

主要方法:

使用CoMFA和CoMSIA进行定量结构-活动关系 (3D-QSAR) 建模.
新分子实体的设计和虚拟选.
在评估包括药物相似性,ADMET特性,分子对接和MM-GBSA.
分子动力学模拟以评估联结蛋白复合体的稳定性.
对设计分子的合成路径的建议.

主要成果:

开发用于TRK抑制的强大的CoMFA和CoMSIA模型.
设计了11种具有更高预测活性的新型印二衍生物.
确定T1,T3和T4是具有强大的TRK抑制潜力的化合物.
通过分子动力学证实联结蛋白复合物的稳定性.
为新型化合物提出可行的合成途径.

结论:

设计的印度-2-衍生物,特别是T1,T3和T4,具有作为TRK抑制剂的显著潜力.
这些化合物代表了开发针对TRK驱动恶性瘤的新抗癌药物的有希望的候选者.
综合计算方法有效地指导了新型,强大的TRK抑制剂的发现.

关键词:

3D-QSAR 是一个3D-QSAR.接收人接收人 MM-gbsa 的意思在TRKs.分子对接的分子对接.分子动力学分子动力学

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