PMID- 16363874
OWN - NLM
STAT- MEDLINE
DCOM- 20060302
LR  - 20071115
IS  - 0739-1102 (Print)
IS  - 0739-1102 (Linking)
VI  - 23
IP  - 4
DP  - 2006 Feb
TI  - In silico structure-based design of a potent and selective small peptide 
      inhibitor of protein tyrosine phosphatase 1B, a novel therapeutic target for 
      obesity and type 2 diabetes mellitus: a computer modeling approach.
PG  - 377-84
AB  - Protein Tyrosine Phosphatase 1B (PTP1B) has been shown to be a negative regulator 
      of insulin signaling by dephosphorylating key tyrosine residues within the 
      regulatory domain of the beta-subunit of the insulin receptor. Recent gene 
      knockout studies in mice have shown the mice to have increased insulin 
      sensitivity and improved glucose tolerance. Furthermore, these mice also 
      exhibited a resistance to diet induced obesity. Inhibitors of PTP1B would have 
      the potential of enhancing insulin action by prolonging the phosphorylated state 
      of the insulin receptor. In addition, recent clinical studies have shown that the 
      haplotype ACTTCAG0 of the PTPN1 gene, which encodes PTP1B, is a major risk 
      contributor to type 2 diabetes mellitus (T2DM). Thus, there is compelling 
      evidence that small molecule inhibitors of PTP1B may be effective in treating 
      insulin resistance at an early stage, thereby leading to a prevention strategy 
      for T2DM and obesity. Based on the crystal structure of the complex of PTP1B with 
      a known inhibitor, we have identified a tetrapeptide inhibitor with the sequence 
      WKPD. Docking calculations indicate that this peptide is as potent as the 
      existing inhibitors. Moreover, the peptide is also found to be selective for 
      PTP1B with a greatly reduced potency against other biologically important protein 
      tyrosine phosphatases such as PTP-LAR, Calcineurin, and the highly homologous 
      T-Cell Protein Tyrosine Phosphatase (TCPTP). Thus the designed tetrapeptide is a 
      suitable lead compound for the development of new drugs against type 2 diabetes 
      and obesity.
FAU - Rao, Gita Subba
AU  - Rao GS
AD  - Department of Biophysics, All India Institute of Medical Sciences, New Delhi - 
      110029, India. gitarao@aiims.ac.in.
FAU - Ramachandran, Manoj V
AU  - Ramachandran MV
FAU - Bajaj, J S
AU  - Bajaj JS
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Biomol Struct Dyn
JT  - Journal of biomolecular structure & dynamics
JID - 8404176
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Ligands)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Oligopeptides)
RN  - EC 3.1.3.48 (PTPN1 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases)
RN  - EC 3.1.3.48 (Ptpn1 protein, mouse)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - Computer Simulation
MH  - Computer-Aided Design
MH  - Crystallography, X-Ray
MH  - Diabetes Mellitus, Type 2/drug therapy/enzymology
MH  - Drug Design
MH  - Enzyme Inhibitors/*chemistry/*pharmacology
MH  - Humans
MH  - Ligands
MH  - Mice
MH  - Models, Molecular
MH  - Multiprotein Complexes
MH  - Obesity/drug therapy/enzymology
MH  - Oligopeptides/*chemistry/*pharmacology
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 1
MH  - Protein Tyrosine Phosphatases/*antagonists & inhibitors/chemistry
MH  - Thermodynamics
EDAT- 2005/12/21 09:00
MHDA- 2006/03/03 09:00
CRDT- 2005/12/21 09:00
PHST- 2005/12/21 09:00 [pubmed]
PHST- 2006/03/03 09:00 [medline]
PHST- 2005/12/21 09:00 [entrez]
AID - d=3024&c=4193&p=13239&do=detail [pii]
AID - 10.1080/07391102.2006.10531233 [doi]
PST - ppublish
SO  - J Biomol Struct Dyn. 2006 Feb;23(4):377-84. doi: 10.1080/07391102.2006.10531233.