Tanwar Omprakash, Tanwar Lalima, Shaquiquzzaman Md, Alam Md Mumtaz, Akhter Mymoona
Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Bioinformatics Infrastructure Facility (BIF), Jamia Hamdard, New Delhi 110062, India.
School of Biochemistry, DAVV, Khandwa Road, Indore, India.
Bioorg Med Chem Lett. 2014 Aug 1;24(15):3447-51. doi: 10.1016/j.bmcl.2014.05.076. Epub 2014 Jun 2.
Inhibition of dipeptidyl peptidase IV (DPP-IV) has been emerged as a promising approach for the treatment of type 2 diabetes (T2D). Structure based virtual screening (SBVS) of Molecular Diversity Preservation International (MDPI) database was performed using Glide and Gold against DPP-IV enzyme. Six promising hits were identified and tested for DPP-IV inhibition. Three compounds were found to be active at low micromolar concentration. The 3-(1-hydrazinyl-1-(phenylamino)ethyl)-4-hydroxy-1-methylquinolin-2(1H)-one (compound A) was found to be the most potent hit with an IC50 of 0.73 μM. These three compounds (A, B and D) were then assessed for their glucose lowering effects in glucose fed hyperglycemic female Wistar rats. The glucose lowering effects of compounds also confirms their potential as anti-diabetic agents. The present study demonstrates a successful utilization of in silico SBVS tools in identification of novel and potential DPP-IV inhibitor.
抑制二肽基肽酶IV（DPP-IV）已成为治疗2型糖尿病（T2D）的一种有前景的方法。使用Glide和Gold针对DPP-IV酶对国际分子多样性保护组织（MDPI）数据库进行基于结构的虚拟筛选（SBVS）。鉴定出六个有前景的命中化合物，并对其进行DPP-IV抑制测试。发现三种化合物在低微摩尔浓度下具有活性。3-(1-肼基-1-(苯基氨基)乙基)-4-羟基-1-甲基喹啉-2(1H)-酮（化合物A）被发现是最有效的命中化合物，IC50为0.73μM。然后评估这三种化合物（A、B和D）对葡萄糖喂养的高血糖雌性Wistar大鼠的降血糖作用。化合物的降血糖作用也证实了它们作为抗糖尿病药物的潜力。本研究证明了在计算机辅助的SBVS工具在鉴定新型和潜在DPP-IV抑制剂方面的成功应用。
