Small molecule interactions with protein-tyrosine phosphatase PTP1B and their use in inhibitor design

Biochemistry
T R BurkeD Barford

Abstract

We have previously shown that a small peptide bearing the hydrolytically stable phosphotyrosyl (pTyr) mimetic, (difluorophosphonomethyl) phenylalanine (F2Pmp), is an extremely potent inhibitor of PTP1B, with an IC50 value of 100 nM [Burke, T. R., Kole, H. K., & Roller, P. P. (1994) Biochem. Biophys. Res. Commun. 204, 129-134]. We further demonstrated that removal of the peptide portion and incorporation of the difluorophosphonomethyl moiety onto a naphthalene ring system, but not a phenyl ring system, resulted in good inhibitory potency [Kole, H. K., Smyth, M. S., Russ, P. L., & Burke, T. R., Jr. (1995) Biochem, J. 311, 1025-1031]. In order to understand the structural basis for this inhibition, and to aid in the design of further analogs, we solved the X-ray structure of [1, 1-difluoro-1-(2-naphthalenyl)-methyl]phosphonic acid (6) complexed within the catalytic site of PTP1B, solved to 2.3 A resolution. In addition to showing the manner in which the phosphonate group is held within the catalytic site, the X-ray structure also revealed extensive hydrophobic interactions with the naphthalene ring system, beyond that possible with an analog bearing a single phenyl ring. It is further evident that, of the two fluorine atoms, the p...Continue Reading

Citations

Mar 30, 2004·Biochemical and Biophysical Research Communications·Julie E ReedBarry V L Potter
Sep 7, 2000·Biochemical Pharmacology·B P Kennedy, C Ramachandran
Jun 14, 2003·Pharmacology & Therapeutics·Kazuo UmezawaTakumi Watanabe
Apr 1, 2000·Bioorganic & Medicinal Chemistry Letters·O A IbrahimiZ Y Zhang
Jun 8, 2001·Bioorganic & Medicinal Chemistry Letters·T R BurkeZ Y Zhang
Aug 28, 2003·Bioorganic & Medicinal Chemistry Letters·Ding-Guo LiuTerrence R Burke
Feb 18, 1999·Bioorganic & Medicinal Chemistry Letters·S W HamJ S Yoo
Mar 28, 2003·Bioorganic & Medicinal Chemistry·Ping HuangCho Tang
Nov 5, 1998·Bioorganic & Medicinal Chemistry·S D TaylorZ Huang
Sep 5, 2002·Nature Reviews. Drug Discovery·Theodore O JohnsonMichael R Jirousek
Jan 25, 2002·Annual Review of Pharmacology and Toxicology·Zhong-Yin Zhang
Nov 2, 2004·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Shiroshi Shibuya
Apr 25, 2000·Archives of Biochemistry and Biophysics·P S SavleP J Kennelly
Mar 29, 2008·Bioorganic & Medicinal Chemistry Letters·Christopher P HolmesJ Russell Grove
Jul 23, 2013·Angewandte Chemie·Theresa LiangTobias Ritter
Jul 31, 2013·Medicinal Research Reviews·Ondřej Baszczyňski, Zlatko Janeba
Apr 13, 2013·The FEBS Journal·Navasona KrishnanNicholas K Tonks
Dec 28, 2004·Journal of Ethnopharmacology·Won Keun OhJong Seog Ahn
Jul 21, 2004·Bioorganic & Medicinal Chemistry Letters·Xianfeng LiAnna K Szardenings
Dec 17, 2005·Bioorganic & Medicinal Chemistry Letters·Long CuiJong Seog Ahn
Aug 27, 2013·Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy·M VenkatachalamG Singaravelu
Oct 21, 2016·Organic & Biomolecular Chemistry·Yujing ZhouJianbo Wang
May 2, 2002·Bioorganic & Medicinal Chemistry·Carmen LeungScott D Taylor
Oct 10, 2009·Colloids and Surfaces. B, Biointerfaces·Sabjan Khaleel BashaGanesan Singaravelu
Mar 22, 2002·The Journal of Biological Chemistry·Lars Fogh IversenNiels Peter Hundahl Moller
Mar 30, 2002·The Journal of Biological Chemistry·Brian E Nordin, Paul Schimmel
Sep 5, 2017·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Tsutomu Yokomatsu
Mar 4, 2000·The Journal of Biological Chemistry·H S AndersenN P Møller
Apr 5, 2000·The Journal of Biological Chemistry·G H PetersN P Moller

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.