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Synthesis, Evaluation and Molecular Docking of Prolyl‐Fluoropyrrolidine Derivatives as Dipeptidyl Peptidase IV Inhibitors
Author(s) -
Sharma Mani,
Gupta Monica,
Singh Divya,
Kumar Manoj,
Kaur Punit
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12142
Subject(s) - docking (animal) , dipeptidyl peptidase , chemistry , biochemistry , stereochemistry , combinatorial chemistry , dipeptidyl peptidase 4 , enzyme , computational biology , biology , medicine , nursing , diabetes mellitus , type 2 diabetes , endocrinology
A series of prolyl‐fluoropyrrolidine derivatives were designed, synthesized and screened for in vitro inhibition of dipeptidyl peptidase IV . The SAR study revealed the influence of substituted chemical modifications on dipeptidyl peptidase IV inhibitory activity. Among all the compounds screened, compound 9 ( IC 50 = 0.83 μ m ) and 10 ( IC 50 = 0.43 μ m ) possessing aryl substituted piperazine with acetamide linker resulted as most potent dipeptidyl peptidase IV inhibitors. Both the compounds 9 and 10 resulted significant reduction in glucose excursion during oral glucose tolerance test in streptozotocin‐induced diabetic rat model at single dose of 10 mg/kg. Molecular docking studies were performed to illustrate the probable binding mode and interactions of prolyl‐fluoropyrrolidine nucleus and its derivatives at binding site of receptor. The fluoropyrrolidine moiety of prolyl‐fluoropyrrolidine derivatives occupied S 1 pocket as observed in the crystal structure ( PDB id: 2 FJP ). The compounds 9 and 10 were observed to occupy S 2 binding pocket and were observed to have interaction with A rg125, T yr547 and S er630 acquired through hydrogen bond. The aryl moiety at piperazine ring was found to extend into the cavity and interacted with A rg358. The observed interactions signalled that occupancy of the highly hydrophobic S 2 pocket is very crucial for dipeptidyl peptidase IV inhibitory activity.