Tautomeric form of ligands in the binding pocket of protein

The vast majority of pharmaceutical active compounds are built from a combination of carbon, phosphate, nitrogen, sulfur and hydrogen atoms. There are physics based methods that are able to identify these atoms at the place of their pharmaceutical effect in proteins. These methods are able to identify all atoms except hydrogens. Typically, this is sufficient to identify where the compound is binding to the protein, but not exactly how, since this depends also very much on the position of the hydrogens. Computational methods and rules help to determine how hydrogens can be distributed in a compound. If there is just one possible solution, the matter is resolved. But, often there are multiple solutions (so called tautomeric forms) and each influences the interaction pattern between a pharmaceutical active compound and its target. Selecting the correct tautomeric form is important - in order to increase the effect or decrease side-effects of drugs chemists analyse the interaction pattern (which is influenced by the placement of hydrogen atoms) between the drug and the protein and try to figure out how to improve it. Using a wrong tautomeric structure can waste a lot of time in the already very time consuming process of developing drugs. At the Memorial Sloan Kettering Cancer Center in New York, USA, the group of John Chodera use advanced computational methods that enable the simulation of every potentially possible hydrogen pattern in a compound and calculate the best interaction pattern. This is possible because their methods use a sophisticated theoretical model adopted for consumer-grad graphic cards. With the help of the algorithms developed in the Chodera group in this project a software solution will be developed that will enable chemists to select the best tautomeric form of a compound. This can help save time and money in the development of drugs.