Identification of Dipeptidyl Peptidase IV Inhibitors: Virtual Screening, Synthesis and Biological Evaluation. (14th May 2014)

• Record Type: Journal Article
• Authors: Xing, Junhao; Li, Qing; Zhang, Shengping; Liu, Haomiao; Zhao, Leilei; Cheng, Haibo; Zhang, Yuan; Zhou, Jinpei; Zhang, Huibin
• Is Part Of: Chemical biology & drug design. Volume 84:Number 3(2014:Sep.)
• Page Start: 364
• Page End: 377
• Publication Date: 2014-05-14
• Subjects: 3D pharmacophore models -- DPP‐4 inhibitors -- multistage virtual screening -- Oral glucose tolerance test -- type‐2 diabetes; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12327
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : Inhibition of dipeptidyl peptidase IV is an important approach for the treatment of type‐2 diabetes. In this study, we reported a multistage virtual screening workflow that integrated 3D pharmacophore models, structural consensus docking, and molecular mechanics/generalized Born surface area binding energy calculation to identify novel dipeptidyl peptidase IV inhibitors. After screening our in‐house database, two hit compounds, HWL‐405 andHWL‐892, having persistent high performance in all stages of virtual screening were identified. These two hit compounds together with several analogs were synthesized and evaluated for in vitro inhibition of dipeptidyl peptidase IV. The experimental data indicated that most designed compounds exhibited significant dipeptidyl peptidase IV inhibitory activity. Among them, compounds35f displayed the greatest potency against dipeptidyl peptidase IV in vitro with the IC50 value of 78 nm . In an oral glucose tolerance test in normal male Kunming mice, compound35f reduced blood glucose excursion in a dose‐dependent manner. Abstract : Several compounds with Tetrahydroisoquinoline scaffold were identified by multi‐stage virtual screening as the antidiabetic drugs candidates against DPP‐4.