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来自对接引导X射线晶体学PYCR1的新型片段抑制剂

Kaylen R Meeks¹, Juan Ji¹, Mykola V Protopopov²

¹Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States.

Journal of chemical information and modeling

|February 27, 2024

概括

研究人员使用结构优先方法发现了新的PYCR1抑制剂. 这些抑制剂通过阻断关键酶结合部位来向癌细胞代谢,为癌症药物开发提供了一条新的途径.

科学领域:

生物化学生物化学
结构生物学结构生物学
癌症新陈代谢癌症新陈代谢

背景情况:

林生物合成酶PYCR1在许多癌症中受到上调.
PYCR1对于癌细胞代谢重编程至关重要.
准PYCR1为癌症治疗提供了一个潜在的策略.

研究的目的:

通过基于片段的,结构优先的方法发现PYCR1的新型抑制剂.
为了识别阻断P5C基质和NADP) H结合位点的化合物.
为PYCR1抑制剂提供片段到优化的基础.

主要方法:

基于碎片的药物发现.
结构第一方法利用对接和X射线晶体学.
选37个类似碎片的碳酸.
动力测试以确定酶抑制.

主要成果:

从37个选的碎片中识别了8个结晶学命中 (22%的命中率).
发现了结合P5C基质和NAD(P) H位点的新型片段.
在动力分析中,四个碎片抑制了PYCR1活性.
一个片段的IC50比现有的类模拟抑制剂低.

结论:

基于碎片的,结构优先的方法对PYCR1抑制剂的发现是有效的.
确定了针对不同结合位点的新型PYCR1抑制剂.
这些发现为开发针对PYCR1.1的新型癌症疗法提供了坚实的基础.

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