A Comparative Study of Successful Central Nervous System Drugs Using Molecular Modeling

Molecular modeling is a powerful tool used for three-dimensional visualization and for exploring electrostatic forces involved in drug transport. This tool enhances student understanding of structure–property relationships, as well as actively engaging them in class. Molecular modeling of several central nervous system (CNS) drugs is used to examine the factors that affect their ability to penetrate the blood–brain barrier. Seventy-eight molecules with known experimental log(BB) values [log(BB) = log(C brain /C blood), where C brain and C blood are the equilibrium molar concentrations of the drug molecule in the brain and the blood, respectively] were selected from the literature and their three-dimensional models constructed using the Spartan software program. For each molecule, the percent polarity was calculated using a space-filling model (PSA%, polar surface area percentage) and an electrostatic potential map that was constructed from the wave function obtained from a single-point energy calculation, using the EDF2 density functional model (PA%, polar area percentage). Plots of these ratios against the experimental log(BB) values clearly display the general trend that the blood–brain barrier penetration decreases as the extent of polarity of a molecule increases. These plots were used to examine the mechanisms for blood–brain barrier penetration by drug molecules belonging to a study set consisting of 10 CNS-active and 3 CNS-inactive drugs. Values of PSA% or PA% greater than ∼15% favor uptake transporter or efflux transporter mediated molecular crossing of the blood–brain barrier. In addition, highly lipophilic drug molecules (PSA% or PA% less than ∼10%) most likely cross the blood–brain barrier by passive diffusion. These results are in agreement with previous experimental studies. Given the relative ease of polar surface area ratio calculations, its influence on drug transport mechanisms is a suitable topic to include in undergraduate curriculum. Several instructional exercises have been included.