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A Library of Thiazolidin‐4‐one Derivatives as Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors: An Attempt To Discover Novel Antidiabetic Agents
Author(s) -
Patel Ashish D.,
Pasha Thopallada Y.,
Lunagariya Paras,
Shah Umang,
Bhambharoliya Tushar,
Tripathi Rati K. P.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000055
Subject(s) - chemistry , docking (animal) , in silico , protein tyrosine phosphatase , virtual screening , stereochemistry , potency , enzyme , molecular model , adme , small molecule , structure–activity relationship , drug discovery , ligand (biochemistry) , binding site , combinatorial chemistry , biochemistry , in vitro , pharmacophore , receptor , medicine , nursing , gene
Protein tyrosine phosphatase 1B (PTP1B) is an important target for the treatment of diabetes. A series of thiazolidin‐4‐one derivatives 8 – 22 was designed, synthesized and investigated as PTP1B inhibitors. The new molecules inhibited PTP1B with IC 50 values in the micromolar range. 5‐(Furan‐2‐ylmethylene)‐2‐(4‐nitrophenylimino)thiazolidin‐4‐one ( 17 ) exhibited potency with a competitive type of enzyme inhibition. structure–activity relationship studies revealed various structural facets important for the potency of these analogues. The findings revealed a requirement for a nitro group‐including hydrophobic heteroaryl ring for PTP1B inhibition. Molecular docking studies afforded good correlation with experimental results. H‐bonding and π–π interactions were responsible for optimal binding and effective stabilization of virtual protein‐ligand complexes. Furthermore, in‐silico pharmacokinetic properties of test compounds predicted their drug‐like characteristics for potential oral use as antidiabetic agents.Additionally, a binding site model demonstrating crucial pharmacophoric characteristics influencing potency and binding affinity of inhibitors has been proposed, which can be employed in the design of future potential PTP1B inhibitors.