Abstract
Reliable information on partition coefficients plays a key role in drug development, as solubility decisively affects bioavailability. In a physicochemical context, the partition coefficient of a solute between two different solvents can be described as a function of solvation free energies. Hence, substantial scientific efforts have been made toward accurate predictions of solvation free energies in various solvents. The grid inhomogeneous solvation theory (GIST) facilitates the calculation of solvation free energies. In this study, we introduce an extended version of the GIST algorithm, which enables the calculation for chloroform in addition to water. Furthermore, GIST allows localization of enthalpic and entropic contributions. We test our approach by calculating partition coefficients between water and chloroform for a set of eight small molecules. We report a Pearson correlation coefficient of 0.96 between experimentally determined and calculated partition coefficients. The capability to reliably predict partition coefficients between water and chloroform and the possibility to localize their contributions allow the optimization of a compound’s partition coefficient. Therefore, we presume that this methodology will be of great benefit for the efficient development of pharmaceuticals.
Highlights
For a sufficiently high bioavailability, a druglike compound generally needs to follow a set of four basic rules, known as Lipinski’s rule of five.[1,2] These simplified guidelines describe the complex interplay of physicochemical properties, which are required for a molecule to act as a drug, including solubility in environments of different polarities
We will refer to these compounds by the single letter code of these biomolecules; that is, we will call the nucleobases as A, G, C, T, and U and 3-methylindole will be referred to as W, p-cresol as Y, and toluene as F in the following. We consider these eight compounds as an ideal set to evaluate the reliability of our grid inhomogeneous solvation theory (GIST) calculations because for all but one (Y) of these compounds, reliable and coherent experimental data are available on their partition coefficients between water and chloroform
We calculated TIP3P and CHCl3 solvation free energies using GAFF. Even when using these parameters, GIST results are lower, by about 2 kcal/mol compared to TI
Summary
For a sufficiently high bioavailability, a druglike compound generally needs to follow a set of four basic rules, known as Lipinski’s rule of five.[1,2] These simplified guidelines describe the complex interplay of physicochemical properties, which are required for a molecule to act as a drug, including solubility in environments of different polarities. Molecules aiming at intracellular targets have to pass through the cell membrane, which is usually facilitated through a certain degree of lipophilicity.[3,4] On the other hand, it is decisive that the molecule features a sufficient number of hydrophilic groups to ensure solubility in the polar intra- and extracellular environments. It is well known that rather lipophilic, that is, “fatty” drugs, such as tetrahydrocannabinol, do show some extent of solubility in polar solvents.[5,6] these drugs can accumulate in fatty tissue, which often is followed by an extended uncontrolled release that causes several adverse effects.[7−10] a balanced equilibrium between solvent preferences, which can be described by the partition coefficient, is of utmost importance in drug design.[11]
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