Design potential selective inhibitors for human leukocyte common antigen-related (PTP-LAR) with fragment replace approach
The overexpression of PTP-LAR could cause the insulin resistance, so PTP-LAR might be a promising target for treating diabetes. In this study, we applied the computer modeling methods with fragment replace approach to screen the fragment database by targeting PTP domain and site B with the aim to discover potent and selective PTP-LAR inhibitors. A series of novel 4-thiazolidone derivatives were gained. The results of their ADMET predictions indicated that these new compounds might become drug candidates. The series of these derivatives were synthesized. Subsequently, their PTP-LAR inhibitory activities were assayed. The compound7d showed highly selectivity for PTP-LAR (10.41 μM) over its close homolog PTP1B (IC50=44.40 μM), SHP2 (IC50>122.81 μM) and CDC25B (IC50>122.81 μM) and docking and molecular dynamics simulation were applied to propose the most likely binding mode of compound7d with PTP-LAR. Thus, our findings reported here may pave a way for discovering potential selective PTP-LAR inhibitors.
AbbreviationsPTP-LAR
Human leukocyte common antigen-related
PTPProtein Tyrosine Phosphatase
IRinsulin receptor
PTP1BProtein tyrosine phosphatase-1B
LRPLung resistance protein
ADMETabsorption, distribution, metabolism, excretion, toxicity
PPBplasma protein binding
BBBblood brain barrier penetration
CYP450cytochrome P450
HIAhuman intestinal absorption
TLCthin-layer chromatography
UVUltra Violet
NMRnuclear magnetic resonance
TMStetramethylsilane
MSmass spectrometry
ANManisotropic network mode
PDBProtein Data Bank
DMFN,N-Dimethylformamide
pNPPpara-nitrophenyl phosphate
DTTdithiothreitol
MDmolecular dynamic
RMSDroot-mean-square deviation
RMSFroot-mean-square fluctuation
SPCsingle-point charge
PMEParticle Mesh Ewald
MM-PBSAmolecular mechanics Poisson Boltzmann surface area
H bond, hydrogen bond
VDWVan der Waals
Human leukocyte common antigen-related
Protein Tyrosine Phosphatase
insulin receptor
Protein tyrosine phosphatase-1B
Lung resistance protein
absorption, distribution, metabolism, excretion, toxicity
plasma protein binding
blood brain barrier penetration
cytochrome P450
human intestinal absorption
thin-layer chromatography
Ultra Violet
nuclear magnetic resonance
tetramethylsilane
mass spectrometry
anisotropic network mode
Protein Data Bank
N,N-Dimethylformamide
para-nitrophenyl phosphate
dithiothreitol
molecular dynamic
root-mean-square deviation
root-mean-square fluctuation
single-point charge
Particle Mesh Ewald
molecular mechanics Poisson Boltzmann surface area
, hydrogen bond
Van der Waals
Communicated by Ramaswamy H. Sarma