胡 琳,雷 妍,李朋华,高 俐,姚晓丹,陈毅坚,左之利.综合运用虚拟筛选三维定量构效关系模型发现潜在 TRPC4 配体[J].中南民族大学学报自然科学版,2018,(4):61-66,114
综合运用虚拟筛选三维定量构效关系模型发现潜在 TRPC4 配体
Discovery of Potential Novel TRPC 4 Inhibitor by Combination of Virtual Screening and 3D-QSAR Modeling
  
DOI:10.12130/znmdzk.20180413
中文关键词: 计算机辅助药物设计  瞬时感受器电位通道 4  抑制剂  虚拟筛选  糖尿病
英文关键词: computer-aided drug design  canonical transient receptor potential  inhibitor  virtual screening  diabetes mellitus
基金项目:国家自然科学基金资助项目(81460553,81760655),中科院战略先导项目(AXDA12030206)
作者单位
胡 琳1,雷 妍1,李朋华2,3,高 俐1,姚晓丹4,陈毅坚1*,左之利2* 中南民族大学 药学院武汉430074 
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中文摘要:
      瞬时感受器电位通道 4( TRPC4) 可能是一种调节人体生理和病理生理功能的关键靶点. 通过计算机辅助药物设计和一系列虚拟筛选方法,结合 Hiphop 药效学团模型,筛选出一系列可能具有良好活性的的 TRPC4 配体化合物,并研究了这些化合物对大鼠胰岛细胞生长的影响. 结果显示,其中新化合物 7 促进了大鼠胰岛细胞的生长,EC50值为 3.58 μmol /L. 然而,化合物 7 对被干扰了 TRPC4 表达的大鼠胰岛细胞的生长无显著性作用. 与此同时,给予化合物 7 后,大鼠胰岛细胞 TRPC4 mRNA 的表达显著降低.因此,化合物 7 可能是一个潜在的 TRPC4 抑制剂,从而可能对糖尿病的治疗起到一定的作用.
英文摘要:
      The modulation of canonical transient receptor potential 4 (TRPC4) may be pivotal in diverse physiological and physiopathological functions in human. To investigate the potential therapeutical roles of novel TRPC4 ligands in diabetes mellitus, a series of compounds with the top rank of Hiphop pharmacophore model and with good fitness were chosen through computer-aided drug design and a series of virtual screening methods. Then, the effects of these compounds were evaluated by bioassay studies on the growth of rat islet cells. The novel compound 7 amoung these compounds promoted the growth of rat islet cells with an EC50 value at 3.58 μmol /L. However, compound 7 failed to show any effect on rat islet cells with TRPC4 knocked down. Meanwhile, the expressions of TRPC4 in mRNA level were significantly decreased after the administration of compound 7 in rat islet cells. Therefore, the therapeutical potential of compound 7 in diabetes mellitus may function through inhibiting TRPC4.
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