An amalgamated molecular dynamic and Gaussian based 3D-QSAR study for the design of 2,4-thiazolidinediones as potential PTP1B inhibitors.
J Mol Graph Model
; 127: 108695, 2024 03.
Article
in En
| MEDLINE
| ID: mdl-38118354
ABSTRACT
Overexpression of protein tyrosine phosphatase 1B (PTP1B) is the major cause of various diseases such as diabetes, obesity, and cancer. PTP1B has been identified as a negative regulator of the insulin signaling cascade, thereby causing diabetes. Numerous anti-diabetic medications based on thiazolidinedione have been successfully developed; however, 2,4-thiazolidinedione (2,4-TZD) scaffolds have been reported as potential PTP1B inhibitors for the manifestation of type 2 diabetes mellitus involving insulin resistance. In the present study, we have employed amalgamated approach involving MD-simulation studies (100 ns) as well as Gaussian field-based 3D-QSAR to develop a pharmacophoric model of 2,4-TZD as potent PTP1B inhibitors. MD simulation studies of the most potent compound in the PTP1B (PDB Id 2QBS) binding pocket revealed that compound 43 was stable in the binding pocket and demonstrated excellent binding efficacy within the active site pocket. MM/GBSA results revealed that compound 43, bearing C-5 arylidine substitution, strongly bound to the target as compared to rosiglitazone with ΔGMM/GBSA difference of -11.13 kcal/mol. PCA, Rg, RMSF, RMSD, and SASA were analyzed from the complex's trajectories to anticipate the simulation outcome. We have suggested a series of 2,4-TZD as possible PTP1B inhibitors based on the results of MD simulation and 3D-QSAR studies.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thiazolidinediones
/
Diabetes Mellitus, Type 2
Limits:
Humans
Language:
En
Journal:
J Mol Graph Model
Journal subject:
BIOLOGIA MOLECULAR
Year:
2024
Document type:
Article
Affiliation country: