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

Research output: Contribution to journalArticle

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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., and 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., and 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 Å 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-difluoro-1-[2-(4- hydroxynaphthalenyl)]methyl]phosphonic acid (8), could potentially replace a water molecule situated in the PT1B·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 (K(i) = 94 μM) relative to parent unsubstituted 6 (K(i) = 179 μM), supporting, in principle, the development of high-affinity 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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Fluorine
Bearings (structural)
Tyrosine
Molecular modeling
Phosphates
Molecules
Catalytic Domain
Hydrogen bonds
Molecular Computers
X-Rays
X rays
Organophosphonates
Peptides
Proteins
Enzymes
Hydrogen Bonding
Phenylalanine
Hydrophobic and Hydrophilic Interactions
Hydroxyl Radical
Inhibitory Concentration 50

ASJC Scopus subject areas

  • Biochemistry

Cite this

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

Small molecule interactions with protein-tyrosine phosphatase PTP1B and their use in inhibitor design. / Burke, Terrence R.; Ye, Bin; Yan, Xinjian; Wang, Shaomeng; Jia, Zongchao; Chen, Li; Zhang, Zhong Yin; Barford, David.

In: Biochemistry, Vol. 35, No. 50, 17.12.1996, p. 15989-15996.

Research output: Contribution to journalArticle

Burke, TR, Ye, B, Yan, X, Wang, S, Jia, Z, Chen, L, Zhang, ZY & Barford, D 1996, 'Small molecule interactions with protein-tyrosine phosphatase PTP1B and their use in inhibitor design', Biochemistry, vol. 35, no. 50, pp. 15989-15996.
Burke TR, Ye B, Yan X, Wang S, Jia Z, Chen L et al. Small molecule interactions with protein-tyrosine phosphatase PTP1B and their use in inhibitor design. Biochemistry. 1996 Dec 17;35(50):15989-15996.
Burke, Terrence R. ; Ye, Bin ; Yan, Xinjian ; Wang, Shaomeng ; Jia, Zongchao ; Chen, Li ; Zhang, Zhong Yin ; Barford, David. / Small molecule interactions with protein-tyrosine phosphatase PTP1B and their use in inhibitor design. In: Biochemistry. 1996 ; Vol. 35, No. 50. pp. 15989-15996.
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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.",
author = "Burke, {Terrence R.} and Bin Ye and Xinjian Yan and Shaomeng Wang and Zongchao Jia and Li Chen and Zhang, {Zhong Yin} and David Barford",
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AU - Chen, Li

AU - Zhang, Zhong Yin

AU - Barford, David

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N2 - 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.

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