Dataset Information

Solvation Thermodynamics in Different Solvents: Water-Chloroform Partition Coefficients from Grid Inhomogeneous Solvation Theory.

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.

SUBMITTER: Kraml J

PROVIDER: S-EPMC7460078 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Solvation Thermodynamics in Different Solvents: Water-Chloroform Partition Coefficients from Grid Inhomogeneous Solvation Theory.

Kraml Johannes J Hofer Florian F Kamenik Anna S AS Waibl Franz F Kahler Ursula U Schauperl Michael M Liedl Klaus R KR

Journal of chemical information and modeling 20200720 8

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 ...[more]

PMID: 32639731

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Project description:The displacement of perturbed water upon binding is believed to play a critical role in the thermodynamics of biomolecular recognition, but it is nontrivial to unambiguously define and answer questions about this process. We address this issue by introducing grid inhomogeneous solvation theory (GIST), which discretizes the equations of inhomogeneous solvation theory (IST) onto a three-dimensional grid situated in the region of interest around a solute molecule or complex. Snapshots from explicit solvent simulations are used to estimate localized solvation entropies, energies, and free energies associated with the grid boxes, or voxels, and properly summing these thermodynamic quantities over voxels yields information about hydration thermodynamics. GIST thus provides a smoothly varying representation of water properties as a function of position, rather than focusing on hydration sites where solvent is present at high density. It therefore accounts for full or partial displacement of water from sites that are highly occupied by water, as well as for partly occupied and water-depleted regions around the solute. GIST can also provide a well-defined estimate of the solvation free energy and therefore enables a rigorous end-states analysis of binding. For example, one may not only use a first GIST calculation to project the thermodynamic consequences of displacing water from the surface of a receptor by a ligand, but also account, in a second GIST calculation, for the thermodynamics of subsequent solvent reorganization around the bound complex. In the present study, a first GIST analysis of the molecular host cucurbit[7]uril is found to yield a rich picture of hydration structure and thermodynamics in and around this miniature receptor. One of the most striking results is the observation of a toroidal region of high water density at the center of the host's nonpolar cavity. Despite its high density, the water in this toroidal region is disfavored energetically and entropically, and hence may contribute to the known ability of this small receptor to bind guest molecules with unusually high affinities. Interestingly, the toroidal region of high water density persists even when all partial charges of the receptor are set to zero. Thus, localized regions of high solvent density can be generated in a binding site without strong, attractive solute-solvent interactions.

Dataset Information

Solvation Thermodynamics in Different Solvents: Water-Chloroform Partition Coefficients from Grid Inhomogeneous Solvation Theory.

Publications

Solvation Thermodynamics in Different Solvents: Water-Chloroform Partition Coefficients from Grid Inhomogeneous Solvation Theory.

Similar Datasets

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