New Software and Approaches for Computer-Aided Drug Discovery

Computers are routinely used in the drug discovery process. Virtual screening is defined to be the selection of compounds by evaluating their desirability in a computational model. Usually the predicted property is the bioactivity of a compound in an in vitro assay. Based on the classic Fischer lock and key-model, virtual screening is either ligand-or structure-based. In three-dimensional virtual screening, models of ligands and/or target proteins are used. In the ligand-based approach, the similarity of known ligands is used in the search for novel structures, whereas in structure-based virtual screening, compounds are docked into a protein model of the drug target. A consideration of all three-dimensions increases the computational expense of virtual screening considerably. The predictions need to be fast, as the commonly used data sets consist of many thousands, even millions of compounds. As virtual screening is a relatively new field of science, there is a need for novel methods and for the improvement of existing virtual screening protocols. In this thesis, a novel ligand-based virtual screening method called FieldChopper was developed. FieldChopper can be used when multiple, similarly binding active compounds are known. This novel method outperformed techniques based on single ligand similarities in a comparative study. In addition, the effects of tautomerism and protonation in structure-based virtual screening were studied with large data sets. It does appear that current methods are not yet accurate enough for separating between different tautomers and protonation sets and therefore the use of multiple forms of molecules in structure-based virtual screening is simply a waste of resources. The effect of conformational analysis approaches on ligand-based virtual screening using shape-based overlay techniques was investigated. It was shown that with GPU computing and single conformation databases that even large databases can be screened on a regular desktop computer. välttämättä optimaalinen ratkaisu. VIII IX Quantity has a quality all of its own.