Discovery of New Dual-Target Agents Against PPAR-γ and α-Glucosidase Enzymes with Molecular Modeling Methods: Molecular Docking, Molecular Dynamic Simulations, and MM/PBSA Analysis

Apr 20, 2024The protein journal

Finding New Compounds That Target Both PPAR-γ and α-Glucosidase Enzymes Using Computer Modeling

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Abstract

Compound 70 exhibited binding energies of -12.16 kcal/mol and -10.07 kcal/mol with PPAR-γ and α-glucosidase enzymes, respectively.

Dual-target agents for PPAR-γ and alpha-glucosidase may provide a promising strategy for Type 2 diabetes treatment.
Molecular modeling techniques were used to design 159 new compounds targeting these enzymes.
Compound 70 demonstrated favorable ADME properties, suggesting its potential for therapeutic use.
Binding energy of compound 70 was more effective than that of reference compounds Acetohexamide and Glibenclamide.
Further analyses indicated that compound 70 had the most favorable binding affinities with both targeted enzymes.

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Type 2 diabetes mellitus (T2DM) has become a serious public health problem both in our country and worldwide, being the most prevalent type of diabetes. The combined use of drugs in the treatment of T2DM leads to serious side effects, including gastrointestinal problems, liver toxicity, hypoglycemia, and treatment costs. Hence, there has been a growing emphasis on drugs that demonstrate dual interactions. Several studies have suggested that dual-target agents for peroxisome proliferator-activated receptor-γ (PPAR-γ) and alpha-glucosidase (α-glucosidase) could be a potent approach for treating patients with diabetes. We aim to develop new antidiabetic agents that target PPAR-γ and α-glucosidase enzymes using molecular modeling techniques. These compounds show dual interactions, are more effective, and have fewer side effects. The molecular docking method was employed to investigate the enzyme-ligand interaction mechanisms of 159 newly designed compounds with target enzymes. Additionally, we evaluated the ADME properties and pharmacokinetic suitability of these compounds based on Lipinski and Veber's rules. Compound 70, which exhibited favorable ADME properties, demonstrated more effective binding energy with both PPAR-γ and α-glucosidase enzymes (-12,16 kcal/mol, -10.07 kcal/mol) compared to the reference compounds of Acetohexamide (-9.31 kcal/mol, -7.48 kcal/mol) and Glibenclamide (-11.12 kcal/mol, -8.66 kcal/mol). Further, analyses of MM/PBSA binding free energy and molecular dynamics (MD) simulations were conducted for target enzymes with compound 70, which exhibited the most favorable binding affinities with both enzymes. Based on this information, our study aims to contribute to the development of new dual-target antidiabetic agents with improved efficacy, reduced side effects, and enhanced reliability for diabetes treatment.

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Discovery of New Dual-Target Agents Against PPAR-γ and α-Glucosidase Enzymes with Molecular Modeling Methods: Molecular Docking, Molecular Dynamic Simulations, and MM/PBSA Analysis

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