来源于天然产物的新型长效DPP-4抑制剂的发现和设计
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- 英文论文题名：Discovery and Rational Design of Natural Product-derived Analogs as Novel and Long-acting DPP-4 Inhibitors
- 论文作者：李诗良 ; 徐洪玲 ; 秦春 ; 张明 ; 单继伟 ; 吴方舒 ; 张有利 ; 尹乔 ; 赵振江 ; 李洪林
- 英文论文作者：Shiliang Li ; Hongling Xu ; Chun Qin ; Ming Zhang ; Jiwei Shan ; Fangshu Wu ; Youli Zhang ; Qiao Yin ; Zhenjiang Zhao ; Honglin Li ; Shanghai Key Laboratory of New Drug Design ; School of Pharmacy ; East China University of Science & Technology
- 年：2016
- 作者机构：上海市新药设计重点实验室/华东理工大学药学院;
- 论文关键词：糖尿病 ; DPP-4 ; 药物设计 ; 天然产物
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第二十八分会：化学生物学
- 语种：中文
- 分类号：TQ460.1
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第二十八分会 ; 化学生物学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：195k
- 原文格式：D
- 会议级别：全国
摘要
糖尿病是当前威胁全球人类健康的最重要的慢性非传染性疾病之一,治疗糖尿病的新型药物的研发是全球关注的热点之一。首个DPP-4抑制剂Sitagliptin在全世界范围内的销售量成功地证明了DPP-4是有效的Ⅱ-型糖尿病治疗靶标。前期采用基于反向对接的计算化学生物学方法发现异瑞香新素对DPP-4表现出中等强度的抑制活性(IC_(50)=14.13μM),它是一个来自瑞香科瑞香属植物金边瑞香的天然产物。本研究以此天然产物为起点,以本课题组发展的SHAFTS分子相似性比较方法为有力工具,开展了骨架跃迁、药效团嫁接等计算机辅助设计,并进一步考虑配体与蛋白质结合位点的静电匹配,高效率地设计并合成出活性提高约7400倍的一类骨架新颖的2-苯基-3,4-二氢-2H-苯并[f]色满-3-胺类DPP4抑制剂。代表性化合物IC_(50)值约为2.0 nM,具有良好的药代动力学性质(口服生物利用度为98%)。体内药效学实验表明,在ob/ob小鼠体内代表性化合物(3 mg/kg)能持续抑制>80%的DPP-4活性超过24小时。进一步的口服葡萄糖耐受实验表明,该化合物改善葡萄糖耐受性的能力与阳性对照Omarigliptin的相当,使其成为具有良好开发前景的靶向DPP-4的长效抗糖尿病候选化合物。
Diabetes is a fast growing worldwide chronic metabolic disorder.DPP-4 has been proved one of the most effective targets for T2 DM treatment by the commercial success of Sitagliptin.Previously,iso-daphnetin,a natural product,was identified to show moderate bioactivity against DPP-4(IC_(50) = 14.13 μM) through a reverse-docking based computational chemical biology approach.In this study,starting from this natural produce,scaffold hopping and pharmacophore grafting were deliberately conducted by using an efficient in house 3D molecular similarity calculation program SHAFTS.Then,the electrostatic complementary between the ligand and the receptor was attentively evaluated.Collectively,those ingenious drug design strategies bring us a series of novel2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors with approximate7400-fold boost in potency.The representative compound shows IC_(50) value around 2.0 nM with good selectivity and excellent pharmacokinetic profiles(F = 98%).In the in vivo efficacy study,this compound displays sustained pharmacodynamic effect with a 3 mg/kg oral dose giving > 80% inhibition of DPP-4 activity within 24 h in ob/ob mice,which is comparable to the performance of the long-acting control Omarigliptin(MK-3102).Moreover,the efficacy of this inhibitor in improving the glucose tolerance is also comparative with Omarigliptin,suggesting itself a promising candidate as long-acting antidiabetic agent targeting DPP-4.
Diabetes is a fast growing worldwide chronic metabolic disorder.DPP-4 has been proved one of the most effective targets for T2 DM treatment by the commercial success of Sitagliptin.Previously,iso-daphnetin,a natural product,was identified to show moderate bioactivity against DPP-4(IC_(50) = 14.13 μM) through a reverse-docking based computational chemical biology approach.In this study,starting from this natural produce,scaffold hopping and pharmacophore grafting were deliberately conducted by using an efficient in house 3D molecular similarity calculation program SHAFTS.Then,the electrostatic complementary between the ligand and the receptor was attentively evaluated.Collectively,those ingenious drug design strategies bring us a series of novel2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors with approximate7400-fold boost in potency.The representative compound shows IC_(50) value around 2.0 nM with good selectivity and excellent pharmacokinetic profiles(F = 98%).In the in vivo efficacy study,this compound displays sustained pharmacodynamic effect with a 3 mg/kg oral dose giving > 80% inhibition of DPP-4 activity within 24 h in ob/ob mice,which is comparable to the performance of the long-acting control Omarigliptin(MK-3102).Moreover,the efficacy of this inhibitor in improving the glucose tolerance is also comparative with Omarigliptin,suggesting itself a promising candidate as long-acting antidiabetic agent targeting DPP-4.
引文
[1]Zhang,S.;Lu,W.;Liu,X.;Diao,Y.;Bai,F.;Wang,L.;Shan,L.;Huang,J.;Li,H.;Zhang,W.Med.Chem.Commun.2011,2(6):471-477.
[2]Liu,X.;Jiang,H.;Li,H.J.Chem.Inf.Model.2011,51(9):2372-2385.
[2]Liu,X.;Jiang,H.;Li,H.J.Chem.Inf.Model.2011,51(9):2372-2385.