Calculating the hydration free energies of organic molecules is a long-standing challenge in computational chemistry as inaccuracy and complexity are major issues. IET, a method for computer modelling of molecular solutions, recently outperformed existing methods in a proof-of-concept study. In its original form, however, IET does not allow accurate calculations of solvation thermodynamics across multiple classes of molecules. The EU-funded IETSOL (Calculation of pharmacokinetic properties of druglike molecules using integral equation theory) project aimed to develop a simpler and more accurate way to predict the hydration free energies using IET of molecular liquids. The method retains information about the solvent structure and estimates the solute chemical potential. Several fundamental breakthroughs increased the accuracy and applicability of 1D and 3D Reference Interaction Site Model (RISM). Scientists could accurately calculate the hydration thermodynamics of the drug-like molecules. An improved description of excluded volume effect was achieved by incorporating two free coefficients. Using the coefficients, the hydration free energies of the drug-like molecules could be calculated with an accuracy of about 1 kcal/mol. The project predicted intrinsic aqueous solubility of 25 crystalline drug-like molecules from different chemical classes with a good accuracy, (correlation coefficient R = 0.85). This is significantly more accurate than that achieved using implicit continuum solvent models. Finally, the relative binding thermodynamics of single-point mutants of a protein-peptide complex (the bovine chymosin-casein complex) was accurately calculated using molecular IET. The density distribution functions computed by molecular IET helped identify the experimentally observed water-binding sites on the surface of chymosin. Due to the importance of solvation and desolvation effects in biological systems, it is anticipated that the developed method will become very useful for biophysical and biomedical predictions.
Predicting, pharmacokinetic, drug, hydration free energy, Integral Equation Theory