Fragmentbaserad in silico design av ligander till G-protein-kopplade receptorer
Tidsperiod: 2017-01-01 till 2017-03-13
Budget: 8 950 000 SEK
G protein-coupled receptors (GPCRs) play important roles in numerous physiological processes and are important drug targets for neurological diseases. Breakthroughs in GPCR structural biology and access to sensitive screening assays provide opportunities to utilize fragment-based lead discovery (FBLD), a powerful approach for drug design. The objective of the project is to create a computational platform for FBLD, with a vision to transform the early drug discovery process for GPCRs. Computational structure-based methods for discovery of fragment ligands and further optimization of these to potent leads will be developed. These techniques will be applied to address two difficult problems in drug discovery. The first of these is to design ligands of peptide-binding GPCRs that have been challenging for existing methods. One of the promises of FBLD is to provide access to difficult targets, which will be explored by combining molecular docking and biophysical screening against neurotensin receptor 1 to identify novel lead candidates. A second challenge is that efficient treatment of neurological disorders often requires modulation of multiple targets. I will develop fragment-based strategies to identify multi-target ligands, focusing on the A2A adenosine receptor and metabotropic glutamate receptor 5. Discovered ligands will represent novel drug candidates against Parkinson’s disease and the developed methods can be applied to numerous GPCR targets.