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An amalgamated molecular dynamic and Gaussian based 3D-QSAR study for the design of 2,4-thiazolidinediones as
Avadh Biharee1, Yogesh Singh1, Swanand Kulkarni1
1Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, Punjab, 151401, India.
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.
Insights
This study developed a pharmacophoric model for 2,4-thiazolidinedione (2,4-TZD) compounds as potent protein tyrosine phosphatase 1B (PTP1B) inhibitors. Compound 43 showed strong binding, offering potential for new anti-diabetic and anti-obesity treatments.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Pharmacology
Background:
- Overexpression of protein tyrosine phosphatase 1B (PTP1B) is linked to diabetes, obesity, and cancer.
- PTP1B negatively regulates insulin signaling, contributing to insulin resistance and type 2 diabetes.
- 2,4-thiazolidinedione (2,4-TZD) scaffolds are investigated as potential PTP1B inhibitors.
Purpose of the Study:
- To develop a pharmacophoric model for 2,4-TZD derivatives as PTP1B inhibitors.
- To identify potent PTP1B inhibitors for treating type 2 diabetes mellitus and related conditions.
Main Methods:
- Employed molecular dynamics (MD) simulations (100 ns) and Gaussian field-based 3D-QSAR.
- Analyzed binding stability and efficacy of compounds within the PTP1B active site (PDB Id: 2QBS).
- Utilized MM/GBSA, PCA, Rg, RMSF, RMSD, and SASA for simulation outcome analysis.
Main Results:
- Compound 43 demonstrated stability and excellent binding efficacy in the PTP1B binding pocket.
- Compound 43 exhibited stronger binding affinity than rosiglitazone, with a ΔGMM/GBSA of -11.13 kcal/mol.
- C-5 arylidine substitution in 2,4-TZD derivatives was identified as a key feature for strong binding.
Conclusions:
- The study successfully developed a pharmacophoric model for 2,4-TZD based PTP1B inhibitors.
- Compound 43 and related derivatives show promise as potential therapeutic agents for PTP1B-related diseases.
- The findings support the development of novel anti-diabetic and anti-obesity drugs targeting PTP1B.
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