title: Identification of dipeptidyl peptidase IV inhibitors: virtual screening, synthesis and biological evaluation.
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 and HWL-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, compounds 35f 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, compound 35f reduced blood glucose excursion in a dose-dependent manner.
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
authors.forename: Junhao
authors.initials: J
authors.lastname: Xing
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Shengping
authors.initials: S
authors.lastname: Zhang
authors.forename: Haomiao
authors.initials: H
authors.lastname: Liu
authors.forename: Leilei
authors.initials: L
authors.lastname: Zhao
authors.forename: Haibo
authors.initials: H
authors.lastname: Cheng
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jinpei
authors.initials: J
authors.lastname: Zhou
authors.forename: Huibin
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001665:Binding Sites; D062126:Databases, Chemical; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D012372:ROC Curve; D013329:Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D018819:Dipeptidyl Peptidase 4
keywords: 3D pharmacophore models; DPP-4 inhibitors; Oral glucose tolerance test; multistage virtual screening; type-2 diabetes