Sensoy’s Lab has been awarded two projects:
1) International European Cooperation in Science and Technology (COST)
2) TUBİTAK 1001 grant
1) Cost Action- CA 15135 :Multi-target paradigm for innovative ligand identification in the drug discovery process (MuTaLig)
The aim of the project is to develop heterobivalent ligands -with fewer side effects- that target Adenosine 2A Receptor (A2AR) pair within the A2AR-D2R heterotetramer for treatment of Parkinson’s disease. We will use a multidisciplinary approach which is composed of three sections:
1. In silico,
2. Synthesis, and
3. In vitro.
To achieve the aim of the project we will;
1) Model the heterotetramer, develop novel heterobivalent ligands which target the heterotetramer and investigate allosteric interactions in silico within the heterotetramer,
2) Identify, synthesize, purify and characterize novel heterobivalent ligands with high binding capacity to the heterotetramer target,
3) Conduct in vitro activity studies (identification of heterobivalent ligands with capability for activating D2R signaling pathway and determination of their optimum doses in cell culture and acute slices, and blood-brain barrier tests).
Within the scope of the project, we will make use of, for the first time, the heterotetrameric structure in an effort to develop more effective therapeutics to alleviate the symptoms of Parkinson’s disease. Besides increasing the quality of life of patients novel molecules will also make important contributions to the economy in terms of usage of lower therapeutic dosage of L-dopa. Moreover, modeling the heterotetramer and determination of amino acid residues in the signaling network will provide valuable information to those who work on the structure-based drug discovery. Lastly, the optimization of synthesis and purification methods as well as in vitro biological tests for the development of novel heterobivalent ligands will constitute good models for future drug discovery studies.
2) TÜBİTAK 1001 : Phosphorylation-Independent Activation of Arrestin by Means of Small Molecules and In-vitro Characterization
The aim of the project is to provide Arr3 with activation as well as specific receptor binding independent of receptor phosphorylation. To this end, we will target regions involved in the activation mechanism of Arr3 by means of small molecules attained from data bases that deposit biologically active small molecules. In this way, abnormal GPCR signalling associated with heart diseases, thyroid, diabetes and cancer can be regulated. The regions involved in the activation mechanism have been published by the principal investigator of the project (Şensoy vd., 2016) and they have been shown to be modulate the function of the protein (Ostermaier vd., 2014; Zhan vd., 2011).
The project is composed of both in silico and in vitro sections. The candidate molecules that can provide phosphorylation independent activation of Arr3 in silico will be tested in vitro by using signaling systems composed of Arr3/active-non-phosphorylated b2AR and Arr3/over-phosphorylated bAR. In this way, the capacity of small molecules in mediating Arr3 to active-non-phosphorylated receptor and modulating the plasma density of active/over-phosphorylated receptor will be evaluated. In addition, the successful small molecules will also be evaluated for their effect on the receptor specificity of phosphorylation-independent Arr3 by using M2R. Our project is original in that it provides alternative solutions to overcome problems associated with current methods used for achieving Arrestin capable of undergoing activation independent of receptor phosphorylation. In addition, the project has also a high scientific impact and it has potential for being transferred to clinical studies since it provides alternative solutions for treatment of autosomal dominant diseases originated from anomalies regarding GPCR phosphorylation.