Rational determination of transfer free energies of small drugs across the water-oil interface.

The application of statistical simulations to the estimation of transfer free energies of pharmacologically relevant organic molecules is reported. Large-scale molecular dynamics simulations have been carried out on a series of four solutes, viz. antipyrine, caffeine, ganciclovir, and alpha-D-glucose, at the water-dodecane interface as a model of a biological water-membrane interfacial system. Agreement with experimentally determined partition coefficients is remarkable, demonstrating that free energy calculations, when executed with appropriate protocols, have reached the maturity to predict thermodynamic quantities of interest to the pharmaceutical world. The computational effort that warrants accurate, converged free energies remains, however, in large measure, incompatible with the high-throughput exploration of large sets of pharmacologically active drugs sought by industrial settings. Compared to the cost-effective, fast estimation of simple partition coefficients, the present free energy calculations, nevertheless, offer a far more detailed information about the underlying energetics of the system when the solute is translocated across the water-dodecane interface, which can be valuable in the context of de novo drug design.