Biophysical Rationale for the Selective Inhibition of PTP1B over TCPTP by Nonpolar Terpenoids

• DOI: 10.1021/acs.jpcb.3c03791
• Publication Date: 2023-09-20T19:14:45Z
• Authors: Anika J. Friedman; Hannah M. Padgette; Levi Kramer; Evan T. Liechty; Gregory W. Donovan; Jerome M. Fox; Michael R. Shirts
• Keywords: T-Lymphocytes; Catalytic Domain; Molecular Dynamics Simulation; Protein Tyrosine Phosphatases; Enzyme Inhibitors; Article; Allosteric Site; Protein Structure, Secondary

Protein tyrosine phosphatases (PTPs) are emerging drug targets for many diseases, including cancer, autoimmunity, and neurological disorders. A high degree of structural similarity between their catalytic domains, however, has hindered the development selective pharmacological agents. Our previous research uncovered two unfunctionalized terpenoid inhibitors that selectively inhibit PTP1B over T-cell PTP (TCPTP), PTPs with sequence conservation. Here, we use molecular modeling, supporting experimental validation, to study basis this unusual selectivity. Molecular dynamics (MD) simulations suggest TCPTP share a h-bond network connects active site distal allosteric pocket; stabilizes closed conformation catalytically essential WPD loop, which it links L-11 loop neighboring α3 α7 helices on other side domain. Terpenoid binding either proximal C-terminal sites─an α β site─can disrupt network; forms stable complex only in PTP1B. In TCPTP, charged residues disfavor at favor site, is conserved proteins. findings thus indicate minor amino acid differences poorly enable binding, property might be enhanced chemical elaboration, illustrate more broadly how conservation neighboring─yet functionally similar─allosteric sites can affect selectivity inhibitory scaffolds (e.g., fragments).