title: Identification of novel PTP1B inhibitors by pharmacophore based virtual screening, scaffold hopping and docking.
abstract: Design and synthesis of protein tyrosine phosphatases-1B (PTP1B) inhibitors are important for the drugs targeted to treat diabetes and obesity. The pharmacophore modeling, docking and scaffold hopping techniques have been applied to discover the novel PTP1B inhibitors. The ten prioritized compounds (115-119, 120-121, 127, 130-131) from the library of 86 compounds were synthesized and found positive in the micro molar range for PTP1B in-vitro inhibitory assays as compared to Suramin (IC50 9.5 μM). Among these five active compounds (115-119) were tested in STZ-s induced diabetic rat model and the most active compound 115 in this test, was further tested in C57BL/KsJ-db/db mice where it significantly improved OGTT along with the fasting and random blood glucose level. The treatment by the compound 115 significantly improved the insulin resistance and insulin signaling by restoring the insulin level and normalizing the serum lipid profile. Compound 115 also augmented the insulin action by modulating the expression of genes involved in insulin signaling like IRS 1-2, PI3K, PTPN1, Akt2, AMPK and PPAR-α. Western blot analysis of both skeletal muscle and liver demonstrated that proteins and intermediate enzymes of insulin signaling were also increased as compared to control group. The compound 115 was also investigated for anti-adipogenic effect on 3T3L-1 cells. The compound 115 inhibited MDI induced lipid accumulation in a dose-dependent manner. The oral bioavailability of compound 115 was ∼10.29% after 30 mg/kg oral dosing assessed in rat.
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Vishal M
authors.initials: VM
authors.lastname: Balaramnavar
authors.affiliation: Division of Biochemistry, Central Drug Research Institute, CSIR, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Rohit
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Division of Biochemistry, Central Drug Research Institute, CSIR, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Rahuja
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Swati
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Division of Biochemistry, Central Drug Research Institute, CSIR, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rawat
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Salil
authors.initials: S
authors.lastname: Varshney
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Hardik
authors.initials: H
authors.lastname: Chandasana
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Chhonker
authors.affiliation: Division of Biochemistry, Central Drug Research Institute, CSIR, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Pawan Kumar
authors.initials: PK
authors.lastname: Doharey
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Biochemistry, Central Drug Research Institute, CSIR, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Gautam
authors.affiliation: Division of Biochemistry, Central Drug Research Institute, CSIR, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Swayam Prakash
authors.initials: SP
authors.lastname: Srivastava
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Rabi Sankar
authors.initials: RS
authors.lastname: Bhatta
authors.affiliation: Division of Biochemistry, Central Drug Research Institute, CSIR, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Jitendra Kumar
authors.initials: JK
authors.lastname: Saxena
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Anil Nilkanth
authors.initials: AN
authors.lastname: Gaikwad
authors.affiliation: Division of Biochemistry, Central Drug Research Institute, CSIR, Jankipuram Extension, Lucknow 226021, UP, India.
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Srivastava
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226021, UP, India. Electronic address: anilsak@gmail.com.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
keywords: Docking; PTP1B inhibitors; Pharmacophore modeling; Scaffold hopping; Synthesis and biological activity