Discovery of inhibitors targeting protein tyrosine phosphatase 1B using a combined virtual screening approach.
Mol Divers
; 26(4): 2159-2174, 2022 Aug.
Article
in En
| MEDLINE
| ID: mdl-34655403
ABSTRACT
Protein tyrosine phosphatase 1B (PTP1B) acts as a therapeutic target for type 2 diabetes. However, the major challenges of PTP1B drug discovery are the poor selectivity and the weak oral bioavailability. In this study, we performed a combined virtual screening approach including multicomplex pharmacophore, molecular docking-based screening, van der Waals energy normalization, pose scaling factor, ADMET evaluation, and molecular dynamics simulation to select PTP1B inhibitors from three databases (PubChem, ChEMBL, and ZINC). We identified three potential PTP1B inhibitors, compounds 1, 4, and 5, with favorable binding energy and good oral bioavailability. The energetic and geometrical analyses show that the three compounds are stably bound to PTP1B, via occupying both the catalytic site (site A) and the proximal noncatalytic site (site B or C). Such occupancy may improve the selectivity. This work not only provided a feasible virtual screening protocol, but also suggested three potential PTP1B inhibitors for the treatment of type 2 diabetes.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Diabetes Mellitus, Type 2
/
Enzyme Inhibitors
/
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Type of study:
Diagnostic_studies
/
Guideline
/
Prognostic_studies
/
Screening_studies
Limits:
Humans
Language:
En
Journal:
Mol Divers
Journal subject:
BIOLOGIA MOLECULAR
Year:
2022
Document type:
Article
Publication country:
HOLANDA
/
HOLLAND
/
NETHERLANDS
/
NL
/
PAISES BAJOS
/
THE NETHERLANDS