The importance of intramolecular hydrogen bonds on the translocation of the small drug piracetam through a lipid bilayer

The number of hydrogen bond donors and acceptors is a fundamental molecular descriptor to predict the oral bioavailability of small drug candidates. In fact, the most widely used oral bioavailability rules (such as the Lipinsky's rule-of-five and the Veber rules) make use of this molecular descriptor. It is generally assumed that hydrogen bond donors and acceptors impact on passive diffusion across cell membranes, a fundamental event during drug absorption and distribution. Although the relationship between the number of these motifs and the probability of having good oral bioavailability has been studied and described for more than 20 years, little attention has been given to their spatial distribution in the molecule. In this paper, we used molecular dynamics to describe the effect of intramolecular hydrogen bonding on the passive diffusion of a small drug (piracetam) through a lipid membrane. The results indicated that the formation of an intramolecular hydrogen bond decreases the barrier for translocation by ca. 4 kcal mol(-1) and increases the permeability of the tested molecule, partially compensating the desolvation penalty arising from the penetration of the drug into the biological membrane core. This effect was apparent in simulations where the formation of this interaction was prevented with the help of modified potentials, and in simulations with a similar compound to piracetam that was not able to form this intramolecular hydrogen bond due to a larger distance between the hydrogen bond donor and acceptor groups. These results were also supported by coarse-grained methods, which are becoming an important resource for sampling a larger chemical space of molecules, with reduced computational effort. Furthermore, entropy and enthalpy derived profiles were also obtained as the compounds translocated across the membrane, suggesting that, even though the process of formation of internal hydrogen bonds is entropically unfavorable, the enthalpic gain is such that the formation of these interactions is beneficial for the passive diffusion across cell membranes.