biostudies-literatureFriedman AJUniversity of Colorado BoulderThink BioscienceNational Institute of General Medical SciencesColorado State UniversityDivision of Chemical, Bioengineering, Environmental, and Transport SystemsNIGMS NIH HHS8305-8316https://www.ebi.ac.uk/biostudies/studies/S-EPMC10694825biostudies-literatureUnknown127(39)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 of selective pharmacological agents. Our previous research uncovered two unfunctionalized terpenoid inhibitors that selectively inhibit PTP1B over T-cell PTP (TCPTP), two PTPs with high sequence conservation. Here, we use molecular modeling, with supporting experimental validation, to study the molecular basis of this unusual selectivity. Molecular dynamics (MD) simulations suggest that PTP1B and TCPTP share a h-bond network that connects the active site to a distal allosteric pocket; this network stabilizes the closed conformation of the catThe journal of physical chemistry. BBiophysical Rationale for the Selective Inhibition of PTP1B over TCPTP by Nonpolar Terpenoids.PMC10694825R35GM143089CBET 1750244R35 GM143089Shirts MRDonovan GWFox JMFriedman AJKramer LPadgette HMLiechty ETfalseBiophysical Rationale for the Selective Inhibition of PTP1B over TCPTP by Nonpolar Terpenoids.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 of selective pharmacological agents. Our previous research uncovered two unfunctionalized terpenoid inhibitors that selectively inhibit PTP1B over T-cell PTP (TCPTP), two PTPs with high sequence conservation. Here, we use molecular modeling, with supporting experimental validation, to study the molecular basis of this unusual selectivity. Molecular dynamics (MD) simulations suggest that PTP1B and TCPTP share a h-bond network that connects the active site to a distal allosteric pocket; this network stabilizes the closed conformation of the cat2023-01-01T00:00:00Z2023 Oct2026-05-28T09:01:01.602Z2025-02-19T04:25:07.021ZS-EPMC106948253772954710.1021/acs.jpcb.3c03791