TY  - JOUR
AU  - Domínguez-Mendoza, Elix Alberto
AU  - Galván-Ciprés, Yelzyn
AU  - Martínez-Miranda, Josué
AU  - Miranda-González, Cristian
AU  - Colín-Lozano, Blanca
AU  - Hernández-Núñez, Emanuel
AU  - Hernández-Bolio, Gloria I.
AU  - Palomino-Hernández, Oscar
AU  - Navarrete-Vazquez, Gabriel
TI  - Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect
JO  - Molecules
VL  - 26
IS  - 4
SN  - 1420-3049
CY  - Basel
PB  - MDPI
M1  - FZJ-2021-06113
SP  - 799 -
PY  - 2021
AB  - 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
LB  - PUB:(DE-HGF)16
C6  - 33557136
UR  - <Go to ISI:>//WOS:000624192300001
DO  - DOI:10.3390/molecules26040799
UR  - https://juser.fz-juelich.de/record/904543
ER  -