Potential therapeutic compounds against hypercholesterolemia: an in-silico analysis
Sara Tahir, Madeeha Khan, Azam Shareef, Hizbullah Khan, Ishrat Jabeen, Ubair Aziz, QuraTul Ain, Mohammad Iqbal Khan, Fouzia Sadiq · Khyber Medical University Journal · 2025
Objective: To identify and evaluate potential alternative compounds targeting HMG-CoA reductase through in-silico methods for the treatment of hypercholesterolemia, aiming for improved safety and pharmacokinetic profiles compared to existing statins. Methods: We employed in-silico analysis to identify molecules that can bind to drug target of statins; 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA reductase) and could be used as potential drugs against hypercholesterolemia and with fewer side effects. Molecular docking analysis of the eight compounds [25-Hydroxycholesterol (25HC), TAK-715, Flufenamic acid, Piceatannol, Retinol, Nortriptyline hydrochloride, Losmapimod and AG555 (tyrphostinb46)] was performed against HMG-CoA to probe the ligand protein interaction profile. Subsequently, molecular dynamics simulation was performed by Maestro in Schrodinger Suite to study the dynamic behavior of each compound. Molinspiration server was utilized for the in-silico drug-likeness and bioactivity while the SwissADME and admetSAR were used for ADMET analysis. Results: All eight repurposed compounds showed favorable binding interactions with HMG-CoA reductase and demonstrated good ADMET properties, including blood-brain barrier permeability, CYP2D6 binding, intestinal absorption, and Caco-2 permeability. TAK-715 and Tyrphostin b46 exhibited the lowest docking scores and stable molecular dynamics, indicating strong binding affinity. Piceatannol showed the most stable ligand-protein complex in RMSF analysis. Drug-likeness and toxicity assessments confirmed the acceptable pharmacokinetic profiles. Overall, TAK-715, Tyrphostin b46, Losmapimod, and Flufenamic acid emerged as the most promising candidates for further exploration in hypercholesterolemia therapy. Conclusion: This study identifies repurposed compounds, particularly TAK-715 and Tyrphostin b46, as promising HMG-CoA reductase inhibitors. Their favorable profiles warrant further experimental validation for hypercholesterolemia treatment.