Design potential selective inhibitors for human leukocyte common antigen-related (PTP-LAR) with fragment replace approach

Abstract

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.

Abbreviations
PTP-LAR	=	Human leukocyte common antigen-related
PTP	=	Protein Tyrosine Phosphatase
IR	=	insulin receptor
PTP1B	=	Protein tyrosine phosphatase-1B
LRP	=	Lung resistance protein
ADMET	=	absorption, distribution, metabolism, excretion, toxicity
PPB	=	plasma protein binding
BBB	=	blood brain barrier penetration
CYP450	=	cytochrome P450
HIA	=	human intestinal absorption
TLC	=	thin-layer chromatography
UV	=	Ultra Violet
NMR	=	nuclear magnetic resonance
TMS	=	tetramethylsilane
MS	=	mass spectrometry
ANM	=	anisotropic network mode
PDB	=	Protein Data Bank
DMF	=	N,N-Dimethylformamide
pNPP	=	para-nitrophenyl phosphate
DTT	=	dithiothreitol
MD	=	molecular dynamic
RMSD	=	root-mean-square deviation
RMSF	=	root-mean-square fluctuation
SPC	=	single-point charge
PME	=	Particle Mesh Ewald
MM-PBSA	=	molecular mechanics Poisson Boltzmann surface area
H bond	=	, hydrogen bond
VDW	=	Van der Waals

Communicated by Ramaswamy H. Sarma

Keywords:

• PTP-LAR
• fragment replace
• synthesis
• docking
• molecular dynamics

Disclosure statement

There is no conflict of interest.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 81773569), the Natural Science Foundation of Tianjin (Grant No. 18JCQNJC13700), the Cooperation and Exchange Project of the National Natural Science Foundation of China (Grant No.81611130090), the Science & Technology Development Fund of Tianjin Education Commission for Higher Education (Grant No. 2017KJ229).