Glycogen phosphorylase (GP) is a rate-limiting allosteric enzyme in the glycogenolysis pathway that contributes to hyperglycemia in type 2 diabetes (T2D). Hence, researchers consider GP a validated target to treat T2D. Commercial antidiabetic drugs are effective but have undesirable effects. Our search for a safer drug led us to investigate a potential GP inhibitor that could modulate blood glucose levels with minimal or no side effects. Herein, we report seven structural analogs of the reference compound N-acetyl-beta-D-glucopyranosyl amine (NBG) (analog of D-glucose) targeting the active site of human liver GPa (PDB ID: 1FC0). In silico molecular docking studies were conducted to predict GPa-ligand interactions. We analyzed drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters using AutoDock 4.2, Discovery Studio, SwissADME, ProTox-II, and ADMETlab web tools. Among all compounds, befunolol (−8.83 kcal/mol) exhibited the highest affinity than NBG (−6.20 kcal/mol) for the binding pocket of GPa and inferred a good pharmacokinetic profile. Toxicological endpoint prediction analysis showed befunolol as a non-hERG blocker and non-carcinogenic with a drug score (0.95) higher than NBG (0.30) and an LD50 value of 922 mg/kg. A molecular dynamics simulation of befunolol and NBG for 100 ns using Schrödinger software revealed the stability of protein-ligand complexes. Overall, our findings suggest that befunolol could represent a potential therapeutic drug candidate worth exploring in cell-based and pre-clinical studies.
Key words: ADMET, Diabetes, Docking, Glycogen Phosphorylase, Inhibitor, MD simulations, ProTox-II,
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