Design, synthesis, biological evaluation and molecular dynamics simulation studies of (R)-5-methylthiazolidin-4-One derivatives as megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2) inhibitors for the treatment of type 2 diabetes

Abstract

PTP-MEG2 plays a significant role in insulin production and is able to enhance insulin signaling and improve insulin sensitivity. So, PTP-MEG2 inhibitors are closely associated with type 2 diabetes therapy. A series of novel (R)-5-methylthiazolidin-4-one derivatives were designed and synthesized, and their PTP-MEG2 inhibitory activities (IC₅₀) were determined. Among the desired compounds, 1h shares the highest inhibitory activity (IC₅₀ = 1.34 μM) against PTP-MEG2. Additionally, various post-dynamic analyses confirmed that when compound 1h bound to the PTP-MEG2, the protein conformations became unstable and the function of the pTyr recognition loop (Asn331-Cys338) would be disturbed. And thus, the ideal conformations needed for the catalytic activity was difficult to be maintained. In brief, these might be how the compound 1h worked. Furthermore, we also found that the key residues Arg332 would play a critical role in disturbing the residue interactions.

Abbreviations
DCCM	=	dynamic cross-correlation mapping
DMF	=	N,N-dimethylformamide
DSSP	=	definition of secondary structure of proteins
FOXO	=	forkhead transcription factors
MD	=	molecular dynamics
PCA	=	principal component analysis
PDB	=	protein data bank
PTKs	=	protein tyrosine kinases
PTPs	=	protein tyrosine phosphatases
PTP-MEG2	=	megakaryocyte protein tyrosine phosphatase 2
RIN	=	residue interaction network
RING	=	Residue Interaction Network Generator
RMSD	=	root means square deviation
RMSF	=	root mean square fluctuation

Communicated by Ramaswamy H. Sarma

Keywords:

• PTP-MEG2
• type 2 diabetes
• De novo design
• synthesis
• molecular dynamics simulation

Disclosure statement

The authors declare that they have no conflict of interest.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (91773569), Natural Science Foundation of Tianjin (16JCZDJC32500 and 18JCQNJC13700) and Science & Technology Development Fund of Tianjin Education Commission for Higher Education (2017KJ229). Furthermore, we are grateful for Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics).