Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• Protein-tyrosine phosphatases (PTPs) are implicated as negative regulators of insulin signaling.
• PTP1B inhibition is a promising therapeutic target for diabetes and obesity, as evidenced by increased insulin sensitivity in knockout mice.

Purpose of the Study:

• To optimize a general PTP inhibitor into a highly selective inhibitor for PTP1B.
• To explore structure-based design strategies for achieving selectivity.

Main Methods:

• Structure-based drug design utilizing PTP mutants and X-ray crystallography.
• Chemical modification of a nonphosphorus, nonpeptide PTP inhibitor (2-(oxalyl-amino)-benzoic acid).

Main Results:

• A highly selective PTP1B inhibitor was developed from a weak general PTP inhibitor.
• Selectivity was achieved by introducing a basic nitrogen, forming a salt bridge with Asp-48 in PTP1B, while causing repulsion in other PTPs with asparagine at the equivalent position.
• The optimized inhibitor maintained a molecular weight below 300 g/mol.

Conclusions:

• Structure-based design can yield highly selective PTP1B inhibitors.
• Targeting residue 48 is a key strategy for achieving PTP1B selectivity.
• The developed inhibitor represents a promising lead compound for diabetes and obesity therapeutics.