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

Jr Burke T.R., B. Ye, X. Yan, S. Wang, Z. Jia, L. Chen, Zhong-Yin Zhang, D. 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
DOIs
StatePublished - 1996
Externally publishedYes

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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., J., Ye, B., Yan, X., Wang, S., Jia, Z., Chen, L., ... Barford, D. (1996). Small molecule interactions with protein-tyrosine phosphate PTP1B and their use in inhibitor design. Biochemistry, 35(50), 15989-15996. https://doi.org/10.1021/bi961256d

Small molecule interactions with protein-tyrosine phosphate PTP1B and their use in inhibitor design. / Burke T.R., Jr; Ye, B.; Yan, X.; Wang, S.; Jia, Z.; Chen, L.; Zhang, Zhong-Yin; Barford, D.

In: Biochemistry, Vol. 35, No. 50, 1996, p. 15989-15996.

Research output: Contribution to journalArticle

Burke T.R., J, Ye, B, Yan, X, Wang, S, Jia, Z, Chen, L, Zhang, Z-Y & Barford, D 1996, 'Small molecule interactions with protein-tyrosine phosphate PTP1B and their use in inhibitor design', Biochemistry, vol. 35, no. 50, pp. 15989-15996. https://doi.org/10.1021/bi961256d
Burke T.R., Jr ; Ye, B. ; Yan, X. ; Wang, S. ; Jia, Z. ; Chen, L. ; Zhang, Zhong-Yin ; Barford, D. / Small molecule interactions with protein-tyrosine phosphate 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., 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 {\AA} 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.",
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T1 - Small molecule interactions with protein-tyrosine phosphate PTP1B and their use in inhibitor design

AU - Burke T.R., Jr

AU - Ye, B.

AU - Yan, X.

AU - Wang, S.

AU - Jia, Z.

AU - Chen, L.

AU - Zhang, Zhong-Yin

AU - Barford, D.

PY - 1996

Y1 - 1996

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., 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.

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