Structural Insights and Binding Mechanism of Synthetic Homo-Palmatine and Homo-Berberine Molecules with P300 Hat Enzyme: A Molecular Dynamics Simulation Study

The palmatine and berberine are the plant-derived isoquinoline alkaloids inhibit p300 HAT enzyme. The homo-palmatine and homo-berberine are the synthetic molecules, the in vitro study shows that these molecules exhibit high inhibition rate against p300 on compared with the parent molecules, the corresponding IC50 values are 0.42 and 1.8 µM respectively. The intermolecular interactions and the binding mechanism of the two molecules with the active site of p300 HAT enzyme are not yet known. The molecular docking analysis has been performed and found that both molecules exactly bind with the active site of p300 HAT enzyme, the binding energy values are -5.76, -5.91 kcal/mol, respectively. Further, the molecular dynamics simulation study shows, the RMSD of homo-berberine and homo-palmatine are not much varied during the simulation and the values are lies between 0.5 to 2.0 A, this indicates the high stability of the molecules in the active site. The binding free energy values have been calculated, found, the energy values of both molecules are almost equal (-35.40, -36.00 kcal/mol). The intermolecular interaction between the homo-berberine and the catalytic site residue (Trp1436) is found to be strong and this contact exists throughout the MD simulation compared with homo-palmatine. These results confirm that homo-berberine can be considered as a potent inhibitor of p300 HAT enzyme compared with homo-palmatine.