Studies of the Mechanism of Selectivity of Protein Tyrosine Phosphatase 1B (PTP1B) Bidentate Inhibitors Using Molecular Dynamics Simulations and Free Energy Calculations

Bidentate inhibitors of protein tyrosine phosphatase 1B (PTP1B) are considered as a group of ideal inhibitors with high binding potential and high selectivity in treating type II diabetes. In this paper, the binding models of five bidentate inhibitors to PTP1B, TCPTP, and SHP-2 were investigated and compared by using molecular dynamics (MD) simulations and free energy calculations. The binding free energies were computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) methodology. The calculation results show that the predicted free energies of the complexes are well consistent with the experimental data. The Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) free energy decomposition analysis indicates that the residues ARG24, ARG254, and GLN262 in the second binding site of PTP1B are essential for the high selectivity of inhibitors. Furthermore, the residue PHE182 close to the active site is also important for the selectivity and the binding affinity of the inhibitors. According to our analysis, it can be concluded that in most cases the polarity of the portion of the inhibitor that binds to the second binding site of the protein is positive to the affinity of the inhibitors while negative to the selectivity of the inhibitors. We expect that the information we obtained here can help to develop potential PTP1B inhibitors with more promising specificity.

[1]  Wei Zhang,et al.  A point‐charge force field for molecular mechanics simulations of proteins based on condensed‐phase quantum mechanical calculations , 2003, J. Comput. Chem..

[2]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[3]  N. Tonks,et al.  Purification of the major protein-tyrosine-phosphatases of human placenta. , 1988, The Journal of biological chemistry.

[4]  Xiaojie Xu,et al.  Predictions of Binding of a Diverse Set of Ligands to Gelatinase-A by a Combination of Molecular Dynamics and Continuum Solvent Models , 2002 .

[5]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[6]  Junmei Wang,et al.  Development and testing of a general amber force field , 2004, J. Comput. Chem..

[7]  P. Kollman,et al.  Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. , 2000, Accounts of chemical research.

[8]  Gang Liu,et al.  Discovery and SAR of novel, potent and selective protein tyrosine phosphatase 1B inhibitors. , 2003, Bioorganic & medicinal chemistry letters.

[9]  K. Sharp,et al.  Calculating the electrostatic potential of molecules in solution: Method and error assessment , 1988 .

[10]  Xiaojie Xu,et al.  Recent Advances in Free Energy Calculations with a Combination of Molecular Mechanics and Continuum Models , 2006 .

[11]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[12]  Gang Liu,et al.  Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Compound 12 Using a Linked-Fragment Strategy , 2003 .

[13]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[14]  John Wagner,et al.  Impaired Bone Marrow Microenvironment and Immune Function in T Cell Protein Tyrosine Phosphatase–deficient Mice , 1997, The Journal of experimental medicine.

[15]  Young-Bum Kim,et al.  Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice , 2000, Molecular and Cellular Biology.

[16]  P. Kollman,et al.  Computational study of protein specificity: The molecular basis of HIV-1 protease drug resistance , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Lirong Chen,et al.  Mapping the Binding Site of a Large Set of Quinazoline Type EGF-R Inhibitors Using Molecular Field Analyses and Molecular Docking Studies. , 2003 .

[18]  D. Barford,et al.  Crystal structure of human protein tyrosine phosphatase 1B. , 1994, Science.

[19]  S. Shoelson,et al.  Crystal Structure of the Tyrosine Phosphatase SHP-2 , 1998, Cell.

[20]  M. Tremblay,et al.  Coordinated action of protein tyrosine phosphatases in insulin signal transduction. , 2002, European journal of biochemistry.

[21]  J. Kusari,et al.  Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction , 1998, Molecular and Cellular Biochemistry.

[22]  M. Lepšík,et al.  Efficiency of a second‐generation HIV‐1 protease inhibitor studied by molecular dynamics and absolute binding free energy calculations , 2004, Proteins.

[23]  A. Moretto,et al.  Bicyclic and tricyclic thiophenes as protein tyrosine phosphatase 1B inhibitors. , 2006, Bioorganic & medicinal chemistry.

[24]  P A Kollman,et al.  Free energy calculations on dimer stability of the HIV protease using molecular dynamics and a continuum solvent model. , 2000, Journal of molecular biology.

[25]  B. Kemp,et al.  The Protein-tyrosine Phosphatase TCPTP Regulates Epidermal Growth Factor Receptor-mediated and Phosphatidylinositol 3-Kinase-dependent Signaling* , 1999, The Journal of Biological Chemistry.

[26]  D. Case,et al.  Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes. , 2003, Journal of molecular biology.

[27]  B. Kennedy,et al.  Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. , 1999, Science.

[28]  P. Kollman,et al.  A well-behaved electrostatic potential-based method using charge restraints for deriving atomic char , 1993 .

[29]  Jeffrey L. Gray,et al.  1 , 2 , 3 , 4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP 1 B inhibitors , 2006 .

[30]  D S Lawrence,et al.  Identification of a second aryl phosphate-binding site in protein-tyrosine phosphatase 1B: a paradigm for inhibitor design. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Ken Chen,et al.  Computational Analysis and Prediction of the Binding Motif and Protein Interacting Partners of the Abl SH3 Domain , 2006, PLoS Comput. Biol..

[32]  Gang Liu,et al.  A Highly Efficient Approach to a Selective and Cell Active PTP1B inhibitors , 2003 .

[33]  Josef M. Penninger,et al.  CD45: new jobs for an old acquaintance , 2001, Nature Immunology.

[34]  Sven Branner,et al.  Structure Determination of T Cell Protein-tyrosine Phosphatase* , 2002, The Journal of Biological Chemistry.

[35]  Ken Chen,et al.  Prediction of binding affinities between the human amphiphysin-1 SH3 domain and its peptide ligands using homology modeling, molecular dynamics and molecular field analysis. , 2005, Journal of proteome research.

[36]  Tingjun Hou,et al.  Molecular dynamics and free energy studies on the wild-type and double mutant HIV-1 protease complexed with amprenavir and two amprenavir-related inhibitors: mechanism for binding and drug resistance. , 2007, Journal of medicinal chemistry.

[37]  M R Lee,et al.  Use of MM‐PB/SA in estimating the free energies of proteins: Application to native, intermediates, and unfolded villin headpiece , 2000, Proteins.