A review of methods for the calculation of solution free energies and the modelling of systems in solution

Abstract

Over the past decade, pharmaceutical companies have seen a decline in the number of drug candidates successfully passing through clinical trials, though billions are still spent on drug development. Poor aqueous solubility leads to low bio-availability, reducing pharmaceutical effectiveness. The human cost of inefficient drug candidate testing is of great medical concern, with fewer drugs making it to the production line, slowing the development of new treatments. In biochemistry and biophysics, water mediated reactions and interactions within active sites and protein pockets are an active area of research, in which methods for modelling solvated systems are continually pushed to their limits. Here, we discuss a multitude of methods aimed towards solvent modelling and solubility prediction, aiming to inform the reader of the options available, and outlining the various advantages and disadvantages of each approach.

Are the Sublimation Thermodynamics of Organic Molecules Predictable?

“…These methods have been previously discussed in a number of publications 10,19,27,106 and are only briefly outlined below. The workflow is outlined in Scheme 1.…”

“…9,17,18 There are now numerous methods to predict solubility, with most varying in how the solvation/hydration step is modeled. Many of these solvation/hydration methodologies have been summarized in a recent review by Skyner et al 19 Commonly, QSPR methods are employed due to their speed, convenience and accuracy, when provided with a suitable training dataset. 10,[20][21][22]23 These methods represent the current state-of-the-art in practical solubility prediction.…”

“…Recently, much work has focused on improving first principles calculation methods of hydration/solvation free energy and has resulted in much improved methods. 19,[32][33][34] Generally, full calculation methods for solubility prediction either use directly, or make reference to, one of the two thermodynamic cycles in Figure 1. We recently presented work showing that these methods, whilst not matching the accuracy of QSPR models, are now capable of reasonable predictions in an acceptable amount of CPU time.…”

Molecular Simulations of Thermodynamic Properties for the Systemα‐Cyclodextrin/Alcohol in Aqueous Solution

“…Molecular dynamics simulations are usually not resorted to when predicting solubility because other methods often require less computational effort [9 -13]. Although these methods may offer very accurate and fast prediction in many cases, their predictive power depends on the chemical structure and definite methods that are best to use are not easy to identify [14,15]. Atomistic simulations have the benefit that they may provide additional conceptual understanding of the underlying molecular level forces driving the solvation process and offer the possibility to obtain a diverse set of physical properties of a complex system based on the same underlying potential energy function (i.e., the molecular force field) which enhances the interpretability of molecular simulation results.…”

A molecular dynamics study of conformations of beta-cyclodextrin and its eight derivatives in four different solvents

“…A recent review is provided by Skyner et al. 68 The average Gsolvation, and the components Gpolar and Gnon-polar are shown in Figure 7. The main contribution to the free energy was observed to be always due to the polar interactions.…”