This project is focused on inhibition of enzyme that is responsible for different functions in human physiology and cancer pathophysiology. In particular, farnesyltransferase enzyme mediates lipid modification reactions to active RAS proteins. From this perspective, in scope of this project, we will make use of computational methods to find possible candidates which can inhibit farnesyltransferase. Thereafter, these molecules will be synthesized and tested in vitro.
RAS protein are guanine nucleotide-dependent molecular switches which mediate cell proliferation, differentiation, growth and survival. Therefore, RAS-activating mutations end up with transformation in cell as a result of either loss of intrinsic activity or GAP-mediated GTPase activity. It is also important to emphasize that RAS proteins are undruggable due to relatively smooth surface with few pocket where molecules might barely bind. Apart from this, novel drug molecules are not able to compete with natural substrates of RAS proteins as well. In scope of our project, we will attempt to understand dynamics of RAS proteins to find a way to modulate intrinsic GTPase activity.
G-protein-coupled receptors (GPCR) are responsible for maintaining communication between cell and its surroundings, which depends on the balance between proper signal initiation and termination. The latter function is fulfilled by Arrestin (Arr) via binding to activated and phosphorylated receptor (desensitization). In spite of being a small family (Arrestin1, 2, 3, and 4), the members display significant differences in their preferences towards the receptor phosphorylation for binding. Here, we aim at providing phosphorylation-independent binding of Arr3 to β2AR by means of small molecules to maintain receptor density on the membrane, hence preventing down-regulation.
In this project we will use heterobivalent ligands for the first time as potent therapeutic drugs to target the tetramer of Adenosine 2A and Dopamine Receptors (A2AR-D2R) involved in the pathology of disease. By doing so, A2AR dimer will be targeted more specifically which might reduce side effects of which are caused by traditional drugs like L-DOPA. To do so, we will investigate allosteric interactions of A2AR-D2R.