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

Terrence R. Burke, Bin Ye, Xinjian Yan, Shaomeng Wang, Zongchao Jia, Li Chen, Zhong Yin Zhang, David Barford

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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)-methyljphosphonic acid (6) complexed within the catalytic site of PTP1B, solved to 2.3 ̊ 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 pro-R α-fluorine interacts with the enzyme to a significantly greater degree than the pro-S α-fluorine, forming a hydrogen bond to Phe 182. On the basis of a computer-assisted molecular modeling analysis, it was determined that addition of a hydroxyl to the naphthyl 4-position, giving [1,1-difluorol-[2-(4-hydroxynaphthalenyl)]methyl]phosphonic acid (8), could potentially replace a water molecule situated in the PTP1B·6 complex, thereby allowing new hydrogen-bonding interactions with Lys 120 and Tyr 46. Compound 8 was therefore prepared and found to exhibit a doubling of affinity (K1 = 94 μM) relative to parent unsubstituted 6 (K1 = 179 μM), supporting, in principle, the development of highaffinity ligands based on molecular modeling analysis of the enzyme-bound parent.

Original languageEnglish (US)
Pages (from-to)15989-15996
Number of pages8
JournalBiochemistry
Volume35
Issue number50
StatePublished - Dec 17 1996

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Burke, T. R., Ye, B., Yan, X., Wang, S., Jia, Z., Chen, L., Zhang, Z. Y., & Barford, D. (1996). Small molecule interactions with protein-tyrosine phosphatase PTP1B and their use in inhibitor design. Biochemistry, 35(50), 15989-15996.