There are two main approaches towards discovery of new therapeutics. We can differ target-based drug design (TBDD), which usually deals with proteins of interest and tries to find various molecules that interact with them, and approach based on phenotype screening, which uses phenotype observation on cells or whole animals. There are also two different approaches towards TBDD - structure-based and ligand-based drug design (SBDD and LBDD, respectively). The lecture will show both the approaches on an example of phosphatidylinositol 4-kineses (PI4Ks), namely phosphatidylinositol 4-kinase IIIb. Our first steps towards the novel inhibitors of this enzyme were purely ligand-based since a structure of the protein was unknown. Lately, our team was able to obtain the crystal structure of this protein, which proved very nice correlation with the structure-activity relationship obtained in our medicinal chemistry efforts and helped us to enhance both activity and selectivity of second-generation inhibitors.