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@ARTICLE{DomnguezMendoza:904543,
      author       = {Domínguez-Mendoza, Elix Alberto and Galván-Ciprés,
                      Yelzyn and Martínez-Miranda, Josué and Miranda-González,
                      Cristian and Colín-Lozano, Blanca and Hernández-Núñez,
                      Emanuel and Hernández-Bolio, Gloria I. and
                      Palomino-Hernández, Oscar and Navarrete-Vazquez, Gabriel},
      title        = {{D}esign, {S}ynthesis, and {I}n {S}ilico {M}ultitarget
                      {P}harmacological {S}imulations of {A}cid {B}ioisosteres
                      with a {V}alidated {I}n {V}ivo {A}ntihyperglycemic {E}ffect},
      journal      = {Molecules},
      volume       = {26},
      number       = {4},
      issn         = {1420-3049},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {FZJ-2021-06113},
      pages        = {799 -},
      year         = {2021},
      abstract     = {Substituted phenylacetic (1–3), phenylpropanoic (4–6),
                      and benzylidenethiazolidine-2,4-dione (7–9) derivatives
                      were designed according to a multitarget unified
                      pharmacophore pattern that has shown robust antidiabetic
                      activity. This bioactivity is due to the simultaneous
                      polypharmacological stimulation of receptors PPARα, PPARγ,
                      and GPR40 and the enzyme inhibition of aldose reductase (AR)
                      and protein tyrosine phosphatase 1B (PTP-1B). The nine
                      compounds share the same four pharmacophore elements: an
                      acid moiety, an aromatic ring, a bulky hydrophobic group,
                      and a flexible linker between the latter two elements.
                      Addition and substitution reactions were performed to obtain
                      molecules at moderated yields. In silico pharmacological
                      consensus analysis (PHACA) was conducted to determine their
                      possible modes of action, protein affinities, toxicological
                      activities, and drug-like properties. The results were
                      combined with in vivo assays to evaluate the ability of
                      these compounds to decrease glucose levels in diabetic mice
                      at a 100 mg/kg single dose. Compounds 6 (a phenylpropanoic
                      acid derivative) and 9 (a benzylidenethiazolidine-2,4-dione
                      derivative) ameliorated the hyperglycemic peak in a
                      statically significant manner in a mouse model of type 2
                      diabetes. Finally, molecular dynamics simulations were
                      executed on the top performing compounds to shed light on
                      their mechanism of action. The simulations showed the
                      flexible nature of the binding pocket of AR, and showed that
                      both compounds remained bound during the simulation time,
                      although not sharing the same binding mode. In conclusion,
                      we designed nine acid bioisosteres with robust in vivo
                      antihyperglycemic activity that were predicted to have
                      favorable pharmacokinetic and toxicological profiles.
                      Together, these findings provide evidence that supports the
                      molecular design we employed, where the unified
                      pharmacophores possess a strong antidiabetic action due to
                      their multitarget activation},
      cin          = {IAS-5 / INM-9},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {33557136},
      UT           = {WOS:000624192300001},
      doi          = {10.3390/molecules26040799},
      url          = {https://juser.fz-juelich.de/record/904543},
}