Abstract
Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway, and more and more studies have shown that it is a potential target for the treatment of type 2 diabetes mellitus (T2DM). In this study, 17 new 4-thiazolinone derivatives were designed and synthesized as novel PTP1B inhibitors, and ADMET prediction confirmed that these compounds were to be drug-like. In vitro enzyme activity experiments were performed on these compounds, and it was found that a plurality of compounds had good inhibitory activity and high selectivity against PTP1B protein. Among them, compound 7p exhibited the best inhibitory activity with an IC50 of 0.92 μM. The binding mode of compound 7p and PTP1B protein was explored, revealing the reason for its high efficiency. In addition, molecular dynamics simulations for the PTP1BWT and PTP1Bcomp#7p systems revealed the effects of compound 7p on PTP1B protein at the molecular level. In summary, the study reported for the first time that 4-thiazolinone derivatives as a novel PTP1B inhibitor had good inhibitory activity and selectivity for the treatment of T2DM, providing more options for the development of PTP1B inhibitors.
Abbreviations | ||
BBB | = | blood-brain barrier |
CDC25B | = | cell division cycle 25 homolog B |
CYP2D6 | = | Cytochrome P450 2D6 binding |
DCCM | = | dynamic cross-correlation map |
DS | = | Discovery Studio |
H bond | = | hydrogen bond |
HIA | = | human intestinal absorption |
LAR | = | leukocyte antigen-related phosphatase |
MD | = | molecular dynamics |
MEG-2 | = | maternal-effect germ-cell defective 2 |
MM-PBSA | = | molecular mechanics Poisson Boltzmann surface area) |
PCA | = | principal component analysis |
PDB | = | Protein Data Bank |
pNPP | = | p–nitrophenyl phosphate |
PPB | = | plasma protein binding |
PTP1B | = | protein tyrosine phosphotase 1B |
RMSD | = | root mean square deviation |
RMSF | = | root mean square fluctuation |
SHP-1 | = | src homologous phosphatase-1 |
SHP-2 | = | src homologous phosphatase-2 |
SPC | = | single-point charge |
TCPTP | = | T cell protein tyrosine phosphatase |
T2DM | = | Type 2 diabetes mellitus |
VDW | = | van der Waals |
Communicated by Ramaswamy H. Sarma
Disclosure statement
The authors report no conflicts of interest in this work.