Permeability-Solubility Compensation by Molecular Dynamics Simulation

The primary motivation for this study is to gain better insight to the prediction of membrane permeability by using molecular dynamics simulation. The present study attempts to evaluate the impact of intermolecular hydrogen bonds between drug molecules on biological activity. We have chosen octanol-water partition coefficient (log Poct) [1] as our starting point because it is measured routinely in pharmaceutical industry. We test whether octanol/water partition coefficients of these drugs correlate with ensemble average membrane permeability’s. All simulations were performed using the GROMACS package. [2] For the initial lipid bilayer structure, a wellequilibrated system containing 128 DPPC lipids was used. Around 7000 water molecules were added to this system to provide the water/membrane ensemble. After about 50 ns of simulation, the aspirin molecules (Fig 1A and 2) are totally aggregated near the center of bilayer. Aspirin occurred in both leaflets because it can transverse the bilayer center spontaneously. Interestingly, the migration process becomes much slower in the case of naproxen (Fig 1B and 2) and equilibrate at the water/DPPC interface even after 110 ns of simulation. We found that changes in the membrane permeability, water solubility, and lipophilicity of drugs depend on strength of the hydrogen bond interaction and geometry of the molecular assemblies.