Drug solubility
The solubility of compounds represent a significant problem in drug discovery research. When large compound collections are screened many compounds with a low solubility tend to be proposed as candidates for new drugs. Unfortunately these low solubility compounds are unsuitable as medicals and can therefore never be developed to drugs. If these compounds could be eliminated at an early stage, either prior to activity screening or early in the hit-to-lead phase when hundreds of hits need to be evaluated, resources could be saved and the lead finding process improved.The definition of drug solubility are log(S) where S is the concentration of the compound in mol/L. Today there are several of different models developed for predicting the solubility and a good summary are presented in the article by Jorgensen and Duffy(Adv. Drug Del. Rev 2002, 54 , 355). Most of the published models uses group contribution, multi-linear regression and Neural network. There have also been at least one model presented using quantum chemical calculation to calculate the drug solubility(J. Comput. Chem 2000, 10 , 1155).
The review by Jorgensen and Duffy also discuss the accuracy of experimental data and there is shown that variation from different laboratories ranged over 0.86 log units. Their conclusion is that the Multi-linear regression methods that are most commonly used can not be better than the experimental accuracy. The most studies shows an rms error of about 0.9. The solubility of drugs are usually divided into two steps, the first one is the the energy for solve a crystal and the second step is from liquid phase to aqueous phase. We are mainly looking at the second step and tries to do improvments there and therfore looking at liquids to avoid the impact of crystals.
Structure determination
Hydrogen bonding is important, plays curical roles in solubility and are usually treated as constants for different kind of groups. We apply both quantum chemistry methods as well as molecular dynamics simulations in combination with spectroscopic tools (IR, Raman, X-ray) to determine the local hydrogen bonding structures.
Aspirine: