Activation of adenosine receptors by orthosteric and allosteric mechanisms

The goals of this project are to understand the activation mechanism of G protein-coupled receptors and design modulators binding to orthosteric and allosteric sites.

We focus on the adenosine receptors, which are involved in essential physiological processes and promising therapeutic targets.

We will first study how binding of ligands to A1 and A2A adenosine receptors influence activation using enhanced sampling molecular dynamics simulations.

Comparison of free energy landscapes describing activation by orthosteric and allosteric ligands will enable us to identify interactions that stabilize specific conformational states and thereby determine signaling.

By combining the simulations with novel biophysical experiments, we will advance understanding of the structural basis of receptor activation.

A1 receptor agonists and positive allosteric modulators are promising candidates for development of drugs against cardiovascular diseases and pain. However, available ligands have unfavorable physicochemical properties or show side effects.

To test our mechanistic model of receptor activation, we will perform virtual screens to identify novel ligand scaffolds with improved properties.

Several hundred million compounds will be screened using a combination of structure-based virtual screening and MD simulations, followed by experimental testing of top-ranked candidates. Hits from the screen will be optimized to identify compounds with efficacy profiles tailored for therapeutic effect.