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基于监督学习,分子对接,分子动力学模拟和生物评估的ASGR1和HMGCR双抑制剂的发现

Yanfeng Liu¹, Liangying Deng², Feng Ding³

¹Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing 211200, China; Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China.

Bioorganic chemistry

|March 13, 2025

概括

研究人员确定了针对3 - 基-3 - 甲基酸-CoA降解酶 (HMGCR) 和亚洲糖蛋白受体1 (ASGR1) 的新型双抑制剂,用于动脉样硬化心血管疾病 (ASCVD) 治疗. 这些化合物显示出作为进一步开发的领先候选人的希望.

科学领域:

生物化学生物化学
药理学药理学是指药理学的学科.
计算化学计算化学

背景情况:

动脉样硬化心血管疾病 (ASCVD) 构成了严重的健康负担.
3-基-3-甲基氨基-CoA降解酶 (HMGCR) 和亚洲糖蛋白受体1 (ASGR1) 被确定为ASCVD的潜在治疗点.

研究的目的:

发现针对HMGCR和ASGR1.1的新型双重抑制剂.
通过in-silico选来确定ASCVD治疗的潜在化合物.

主要方法:

使用了基于联体的监督学习,分子对接和分子动力学模拟的组合.
选了Chemdiv和SPECS分子数据库的潜在双重抑制剂.
对HMGCR的评估化合物抑制率和与ASGR1.1的结合亲和力.

主要成果:

确定了三种化合物 (8006-6092,K007-0721,D011-1471) 显示HMGCR和ASGR1.1的双重抑制.
化合物K007-0721对ASGR1显著结合 (Kd = 67.63μM) 和显著的HMGCR抑制 (61.48%).
化合物对HMGCR和ASGR1.1的解离常数表现出不同的抑制率.

结论:

已识别的双重抑制剂代表了进一步优化的有希望的候选者.
这些化合物具有开发针对ASCVD的新治疗策略的潜力.

关键词:

3-基-3-甲基氨基-CoA减少酶 (HMGCR) 是一种亚洲糖蛋白受体1 (ASGR1) 是一种亚洲糖蛋白受体.双目标抑制剂双目标抑制剂分子对接是分子对接.分子动力学模拟模型

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