Taylor & Francis Group
Browse
tbsd_a_1699862_sm6530.docx (815.42 kB)

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

Download (815.42 kB)
Version 2 2019-12-09, 13:02
Version 1 2019-12-02, 08:28
journal contribution
posted on 2019-12-09, 13:02 authored by Jing-Wei Wu, Huan Zhang, Wei-Ya Li, Xue Tang, Hong-Lian Li, Xin-Hua Lu, Zhi-Hui Zheng, Ying Ma, Run-Ling Wang

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

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

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

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).

History