The role of structure based virtual screening in the early phase of drug discovery

Identification of a viable lead is a critical step in drug discovery. The qualities of the lead set the stage for subsequent efforts to ameliorate therapeutic efficacy through potency, selectivity, pharmacokinetics, toxicity and side effects. In a retrospective view of drug research the lead identification has been realised mainly by in vivo methodologies. However, limitations of in vivo models were found to be critical factors when analysing attrition rates that prompted research groups to introduce in vitro tests and rational approaches at the frontline of discovery programs. Virtual screening (VS) methods merge in vitro high-throughput (HTS) and rational approaches. The VS methods can be classified as ligand and structure based techniques. Structure based approaches depart from the structural information of the target to identify potential interactions between the ligands and the protein. The advantages and disadvantages and the applicability of the structure based virtual screening approaches constituted the main aim of my studies. The glycogen synthase kinase 3beta (GSK-3beta), the beta-secretase and the c-jun N-terminal kinase 3 (JNK-3) were selected as primary targets for virtual screening. The performance of virtual screens can only be validated in parallel with HTS, therefore a head to head comparative analysis was my next goal.