综合性药物设计使用理性,药基相映射和分子对接使用新型的基衍生物
Anuradha Mehra1, Amit Mittal1, Rahul Sharma1
1Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalan-dhar-Delhi G.T. Road (NH-1), Phagwara (Punjab) 144411, India.
新型葡萄糖激酶激活剂旨在治疗2型糖尿病,具有高结合亲和力和低毒性. 这些有前途的化合物为管理高血糖症提供了潜在的新治疗途径.
科学领域:
- 药用化学 医学化学
- 计算机化药物设计技术
- 药理学 药理学是指药理学的学科.
背景情况:
- 2型糖尿病的特征是高血糖,原因是胰岛素抵抗或胰岛素分泌受损.
- 葡萄糖激酶激活剂 (GKA) 是2型糖尿病管理的有前途的治疗点.
- 最近在日本批准多尔扎格利亚丁,突出了GKA的临床潜力.
研究的目的:
- 设计新的葡萄糖激酶激活剂 (GKA),以改善2型糖尿病的管理.
- 为了减轻与传统糖尿病药物相关的副作用.
- 识别具有增强的药理动力学和安全性特征的化合物.
主要方法:
- 从ZINC数据库中,虚拟选了56种结构类似于1--硫) -1-H-英多尔-2-碳酸的化合物.
- 使用AutoDock Vina进行分子对接,以评估与GK受体的结合亲和力.
- 使用瑞士ADME和使用PKCSM的毒性概况的药理动力学特性 (ADME) 的in silico预测.
- 密度函数理论 (DFT) 分析用高斯式16进行化合物稳定性评估.
主要成果:
- 化合物RS33和RS37对GK受体具有很高的结合亲和力 (分别为8.93和8.44卡路里/mol).
- RS33和RS37遵循利宾斯基规则,这表明口服吸收和分泌有利.
- 与Dorzagliatin和MRK相比,RS33和RS37没有表现出AMES毒性,皮肤敏感性或肝毒性.
- 化合物RS43在DFT分析 (高ΔE, η, χ) 的基础上显示出最高的稳定性.
结论:
- 经过计算设计的分子表现出优越的结合亲和力和有利的药理动力学特征.
- 这些新型的GKA显示出最小的毒性,表明有前途的安全性.
- 已识别的化合物是进一步临床前开发的强有力的候选者,作为2型糖尿病的葡萄糖激酶激活剂.
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