Integrated Approach to Identify Selective PTP1B Inhibitors Targeting the Allosteric Site

Protein tyrosine phosphatase 1B (PTP1B)
is an intractable target
for drug discovery due to its conservative and cationic catalytic
site. Targeting alternative allosteric sites of PTP1B is a promising
strategy to achieve specificity and bioavailability. A hierarchical
virtual screening based on a previously identified allosteric site
was applied to search for potential PTP1B inhibitors with better pharmacological
profiles. Four potent PTP1B inhibitors (H1, H3, H7, and H9) with structures distinct
from known inhibitors were identified. Among them, H3 and H9 demonstrated evident selectivity to PTP1B over
homologous T-cell protein tyrosine phosphatase (TCPTP) and SHP2. Molecular
dynamics simulations and molecular mechanics-generalized Born surface
area (MM-GBSA) calculations recognized Phe280, Phe196, Leu192, and
Asn193 as key residues responsible for potent allosteric inhibition
and excellent PTP selectivity. The results not only expand the structural
diversity but also aid the future molecular design of PTP1B allosteric
inhibitors.