title: Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B.
abstract: Several protein-tyrosine phosphatases (PTPs) have been proposed to act as negative regulators of insulin signaling. Recent studies have shown increased insulin sensitivity and resistance to obesity in PTP1B knockout mice, thus pointing to this enzyme as a potential drug target in diabetes. Structure-based design, guided by PTP mutants and x-ray protein crystallography, was used to optimize a relatively weak, nonphosphorus, nonpeptide general PTP inhibitor (2-(oxalyl-amino)-benzoic acid) into a highly selective PTP1B inhibitor. This was achieved by addressing residue 48 as a selectivity determining residue. By introducing a basic nitrogen in the core structure of the inhibitor, a salt bridge was formed to Asp-48 in PTP1B. In contrast, the basic nitrogen causes repulsion in other PTPs containing an asparagine in the equivalent position resulting in a remarkable selectivity for PTP1B. Importantly, this was accomplished while retaining the molecular weight of the inhibitor below 300 g/mol.
authors.affiliation: Protein Chemistry, Novo Nordisk, DK-2880 Bagsvaerd, Denmark. lfiv@novo.dk
authors.forename: L F
authors.initials: LF
authors.lastname: Iversen
authors.forename: H S
authors.initials: HS
authors.lastname: Andersen
authors.forename: S
authors.initials: S
authors.lastname: Branner
authors.forename: S B
authors.initials: SB
authors.lastname: Mortensen
authors.forename: G H
authors.initials: GH
authors.lastname: Peters
authors.forename: K
authors.initials: K
authors.lastname: Norris
authors.forename: O H
authors.initials: OH
authors.lastname: Olsen
authors.forename: C B
authors.initials: CB
authors.lastname: Jeppesen
authors.forename: B F
authors.initials: BF
authors.lastname: Lundt
authors.forename: W
authors.initials: W
authors.lastname: Ripka
authors.forename: K B
authors.initials: KB
authors.lastname: Møller
authors.forename: N P
authors.initials: NP
authors.lastname: Møller
mesh_terms: D000818:Animals; D001216:Asparagine; D001224:Aspartic Acid; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008968:Molecular Conformation; D008970:Molecular Weight; D010070:Oxalates / Q000737:chemistry* / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D062367:ortho-Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology*; D018909:src Homology Domains
chemical_list: C405943:2-(oxalylamino)benzoic acid; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D010070:Oxalates; D062367:ortho-Aminobenzoates; D001224:Aspartic Acid; D001216:Asparagine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse