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综合计算和基于生物传感器的策略,用于发现全性SMYD3配体,使用perodon作为起点

Edward A FitzGerald¹, Moira M Rachman², Daniela Cederfelt³

¹Department of Chemistry - BMC, Uppsala University, Uppsala, Sweden; Beactica Therapeutics, Virdings allé 2, Uppsala, Sweden.

Bioorganic & medicinal chemistry

|March 2, 2025

概括

研究人员为SMYD3 (含有蛋白3的SET和MYND域) 确定了新的全osteric连接体,这是一个涉及癌症的表观遗传酶. 这一发现有助于通过探索非催化功能来开发向癌症疗法.

科学领域:

生物化学生化学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.
药物发现药物发现药物发现

背景情况:

SMYD3 (含有蛋白3的SET和MYND域) 是一种涉及癌症发展的表观遗传酶.
针对SMYD3的活性位点抑制剂已经显示出抗瘤活性.
开发针对非催化功能的配体提供了一个替代的治疗策略,避免保留的活性位点.

研究的目的:

使用计算建模探索SMYD3的全结合部位.
为了从商业化合物库中识别新的SMYD3配体.
开发干扰非催化 SMYD3 功能的连接体.

主要方法:

在SMYD3.3上计算模拟perodon结合部位.
在商业化合物库中对SMYD3类似物进行选.
时间分辨格合干扰测量 (GCI) 生物传感器分析以评估连接体结合.
基于碎片的药物设计,通过破碎perodon和生长识别的碎片.

主要成果:

鉴定出两种具有与SMYD3相似的结合亲缘关系的peperodon类似物.
基于碎片的查确定了N-phenylformamide和三种结合SMYD3.3的相关化合物.
与perodon相比,这些新型连接体表现出更高的亲和力和更高的连接体效率.
由于其灵活的结构,SMYD3结合点的结合能力较差,阻碍了进一步的结构研究.

结论:

计算机建模和生物传感器分析成功识别了新的全性SMYD3配体.
鉴定到的配体为开发针对非催化SMYD3功能的新型癌症疗法提供了潜力.
尽管SMYD3结构面临挑战,但这种方法有效地使用最小的资源产生了新的化合物.

关键词:

计算建模计算建模表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.基于碎片的药物发现.在SMYD3中,在SPR生物传感器.

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