Hydration Free Energy as a Molecular Descriptor in Drug Design: A Feasibility Study

Abstract

In this work the idea was investigated whether calculated hydration energy (ΔGhyd ) can be used as a molecular descriptor in defining promising regions of chemical space for drug design. Calculating ΔGhyd using the Density Solvation Model (SMD) in conjunction with the density functional theory (DFT) gave an excellent correlation with experimental values. Furthermore, calculated ΔGhyd correlates reasonably well with experimental water solubility (r(2) =0.545) and also log P (r(2) =0.530). Three compound collections were used: Known drugs (n=150), drug-like compounds (n=100) and simple organic compounds (n=140). As an approximation only molecules, which do not de/protonate at physiological pH were considered. A relatively broad distribution was seen for the known drugs with an average at -15.3 kcal/mol and a standard deviation of 7.5 kcal/mol. Interestingly, much lower averages were found for the drug-like compounds (-7.5 kcal/mol) and the simple organic compounds (-3.1 kcal/mol) with tighter distributions; 4.3 and 3.2 kcal/mol, respectively. This trend was not observed for these collections when calculated log P and log S values were used. The considerable greater exothermic ΔGhyd average for the known drugs clearly indicates in order to develop a successful drug candidate value of ΔGhyd <-5 kcal/mol or less is preferable.

Approaches for Calculating Solvation Free Energies and Enthalpies Demonstrated with an Update of the FreeSolv Database

“…15–21 Hydration free energies themselves are valuable quantities in drug design 43,78 and can be used to understand the impact of ligand desolvation on the binding process 79,80 or can be utilized as QSAR descriptors. 81 …”

Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents

“…The other mainstream descriptors: molecular weight (MW), hydrogen bond donors (HD), hydrogen bond acceptors (HA) polar surface area (PSA) and rotatable bonds (RB) (see Table S1 in the Supplementary Materials ) are all within the drug-like chemical space. It has been previously noted that the currently-used molecular descriptors like log P and log S do not entirely capture the required water solubility profiles of successful drugs [ 17 ].…”

Computational Studies on the Molecule 1-(2-Hydroxyethyl)-5-Fluorouracil in Gas Phase and Aqueous Solution and Prediction of Its Confinement inside Capped Nanotubes

“…The increase in the degree of solubility in water of the studied molecule in comparison to 5-FU molecule is probably induced by the presence of the 1-(2-hydroxyethyl) fragment. Recently, Zafar et al [50] have estimated the range of Gibbs free energy of solvation in drug design; they have reported that the ûG sol value of quality drug candidates should be less than −12 Kcal/mol. the ûG sol value of the studied molecule is much less than −12 Kcal/mol.…”