Identification of novel PTP1B inhibitors by pharmacophore based virtual screening, scaffold hopping and docking.
作者： Vishal M. Balaramnavar , Rohit Srivastava , Neha Rahuja , Swati Gupta , Arun K. Rawat
DOI: 10.1016/J.EJMECH.2014.09.097
关键词:
摘要: Design and synthesis of protein tyrosine phosphatases-1B (PTP1B) inhibitors are important for the drugs targeted to treat diabetes obesity. The pharmacophore modeling, docking scaffold hopping techniques have been applied discover novel PTP1B inhibitors. ten prioritized compounds (115-119, 120-121, 127, 130-131) from library 86 were synthesized found positive in micro molar range in-vitro inhibitory assays as compared Suramin (IC50 9.5 μM). Among these five active (115-119) tested STZ-s induced diabetic rat model most compound 115 this test, was further C57BL/KsJ-db/db mice where it significantly improved OGTT along with fasting random blood glucose level. treatment by insulin resistance signaling restoring level normalizing serum lipid profile. Compound also augmented action modulating expression genes involved like IRS 1-2, PI3K, PTPN1, Akt2, AMPK PPAR-α. Western blot analysis both skeletal muscle liver demonstrated that proteins intermediate enzymes increased control group. investigated anti-adipogenic effect on 3T3L-1 cells. inhibited MDI accumulation a dose-dependent manner. oral bioavailability ∼10.29% after 30 mg/kg dosing assessed rat.
sci-hub.se 参考文章(82)
Barry J. Goldstein, Faiyaz Ahmad, Wendi Ding, Pei-Ming Li, Wei-Ren Zhang, Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases Insulin Action. ,vol. 182, pp. 91- 99 ,(1998) , 10.1007/978-1-4615-5647-3_10
Gerhard Klebe, Ute Abraham, Comparative molecular similarity index analysis (CoMSIA) to study hydrogen-bonding properties and to score combinatorial libraries. Journal of Computer-aided Molecular Design. ,vol. 13, pp. 1- 10 ,(1999) , 10.1023/A:1008047919606
Wolfgang Sippl, Development of biologically active compounds by combining 3D QSAR and structure-based design methods. Journal of Computer-aided Molecular Design. ,vol. 16, pp. 825- 830 ,(2002) , 10.1023/A:1023888813526
Peter Blume-Jensen, Tony Hunter, Oncogenic kinase signalling. Nature. ,vol. 411, pp. 355- 365 ,(2001) , 10.1038/35077225
U Kragh-Hansen, Molecular aspects of ligand binding to serum albumin. Pharmacological Reviews. ,vol. 33, pp. 17- 53 ,(1981)
Bin Liu, Ying Guo, Jun Wang, Rui Xu, Xin Wang, Dan Wang, Liqun Zhang, Yongnan Xu, None, Spectroscopic studies on the interaction and sonodynamic damage of neutral red (NR) to bovine serum albumin (BSA) Journal of Luminescence. ,vol. 130, pp. 1036- 1043 ,(2010) , 10.1016/J.JLUMIN.2010.01.021
Bei B. Zhang, Gaochao Zhou, Cai Li, AMPK: An Emerging Drug Target for Diabetes and the Metabolic Syndrome Cell Metabolism. ,vol. 9, pp. 407- 416 ,(2009) , 10.1016/J.CMET.2009.03.012
Ping Huang, John Ramphal, James Wei, Congxin Liang, Bahija Jallal, Gerald McMahon, Cho Tang, Structure-based design and discovery of novel inhibitors of protein tyrosine phosphatases. Bioorganic & Medicinal Chemistry. ,vol. 11, pp. 1835- 1849 ,(2003) , 10.1016/S0968-0896(03)00039-7
M Zasloff, JI Williams, Q Chen, M Anderson, T Maeder, K Holroyd, S Jones, W Kinney, K Cheshire, M McLane, A spermine-coupled cholesterol metabolite from the shark with potent appetite suppressant and antidiabetic properties. International Journal of Obesity. ,vol. 25, pp. 689- 697 ,(2001) , 10.1038/SJ.IJO.0801599
Renxiao Wang, Yipin Lu, Shaomeng Wang, Comparative evaluation of 11 scoring functions for molecular docking. Journal of Medicinal Chemistry. ,vol. 46, pp. 2287- 2303 ,(2003) , 10.1021/JM0203783