Defined-sector explicit solvent in the continuum model approach for computational prediction of p K

Accurate prediction of the acidity dissociation constant (K a) is a challenge for the theory of proton-transfer reactions, making first-principles prediction of pK a within 0.5 pK units of experimental values a benchmark of broad interest. In the present contribution, the defined-sector explicit solvent in continuum cluster model, which considers the structure-to-chemical affinity relationship of the carboxyl functional group, is presented. The model demonstrates predictable solvent networks based on established ‘preferred’ conformations found in a training set. Predictability within 1 kcal mol–1 accuracy is shown for a full set of carboxylic acid systems with varying functionality

Intestinal solubility and absorption of poorly water soluble compounds: predictions, challenges and solutions

We have explored for which type of compounds biorelevant dissolution profiling in simulated intestinal fluids would accurately predict solubility in human intestinal fluid. In total, 460 solubility values in simulated and aspirated human intestinal fluid for 78 drugs were compiled and analyzed. Significant solubilization in the colloidal structures was obtained in fasted and fed state fluids for drug compounds with a logD(oct)&gt;3. Highly lipophilic compounds with high melting points (Tm &gt; 200 °C) could also be significantly solubilized, but typically such compounds had solubility values in the lower µg/ml range also in the presence of the colloidal structures. On the basis of our analysis, compounds with a logD(oct)&gt;3 should be explored in biorelevant dissolution media to better predict in vivo performance after oral dosing.</p