Integrated docking, molecular dynamics, and Markov state modelling reveal epigenetic target engagement by anti-obesity drugs

Epigenetic regulators such as DNA methyltransferase 3 alpha (DNMT3A), p300 histone acetyltransferase (HAT), and histone deacetylase 3 (HDAC3) govern adipocyte differentiation, lipid metabolism, and metabolic memory, contributing to obesity progression. However, whether approved anti-obesity drugs directly modulate these enzymes remains unclear. This study evaluated five FDA-approved agents—bupropion, naltrexone, orlistat, phentermine, and topiramate—against DNMT3A, p300, and HDAC3 using molecular docking, molecular dynamics simulations, Markov state modeling, PCA, free-energy landscape analysis, DCCM, RMSF, and MM-GBSA calculations. Distinct ligand-specific interactions were observed. Orlistat and phentermine showed stable binding and favorable energetics with DNMT3A, engaging catalytic residues and restricting flexibility. In p300, orlistat and topiramate stabilized regions involved in acetyl-CoA and substrate positioning. For HDAC3, only orlistat and topiramate maintained stable binding, with orlistat showing the most favorable energetics within the catalytic tunnel and Zn2+-associated region. Overall, orlistat—followed by topiramate and phentermine—most effectively stabilized catalytically relevant conformations. These findings indicate that certain anti-obesity drugs may exert epigenetic effects, influencing adipocyte function and metabolic regulation, warranting further experimental validation.