Dynamic pharmacophores for the discovery of specific modulators of G protein-coupled receptors.

• Applicant: Professor Dr. Marcel Bermudez
• Subject Area: Pharmacy
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407626949

G protein-coupled receptors (GPCR) are integrative and highly complex signaling machineries. Due to their abundance and relevance in regulating the majority of (patho-) physiological processes they represent the most important drug target class covering a wide range of therapeutic fields. Despite remarkable biological relevance, understanding of the underlying signaling mechanisms is still incomplete, which is attributed to its complex nature. GPCRs can trigger multiple signaling pathways like G protein-activation or recruitment and activation of β-arrestins. Given the complexity of GPCR signaling and the potential therapeutic benefit of controlling them, there is a need for specific modulators as both pharmacological tools and drug candidates. This includes ligands with (I) a specific binding profile at distinct receptors, (II) various levels of receptor activation, (III) functional selectivity (also referred to as biased signaling) and (IV) allosteric receptor modulation. Therefore, mechanistic understanding of ligand-dependent receptor activation resulting in ligand-specific GPCR signaling currently represents a central challenge in medicinal chemistry and pharmacology. The aim of this project is to identify GPCR modulators that are tailored towards a specific receptor function in a rational manner. To reach this goal, a novel modeling strategy will be implemented, which combines established in silico strategies with MD simulations to incorporate GPCR dynamics as a source for specific functionality. This interdisciplinary project will benefit from close collaborations that provide pharmacological data for experimental feedback cycles. Three GPCR families will be subject for this study, (i) muscarinic receptors (MR), (ii) opioid receptors (OR) and (iii) adenosine receptors (AR), because of their therapeutic relevance and available structural data.To reach the goal to discover specific GPCR modulators, the following milestones were defined: First, mechanistic models for a rational explanation of specific GPCR functions will be established by means of docking and extensive MD simulations guided by experimental data. Second, we will generate predictive models for ligand-dependent GPCR function based on the concept of dynamic pharmacophore models. This novel modeling approach combines chemical feature-based interaction models with MD simulations in a fully automated way. Third, novel GPCR modulators with tailored functionality will be identified by virtual screening based on mechanistic dynamic pharmacophores.The novelty of this project lays in the prospective identification of ligands with a tailored function by incorporating mechanistic knowledge and receptor dynamics in a virtual screening workflow. Tailor-made GPCR modulators provide novel therapeutic options for a multitude of pathological conditions and can lead to safer and more efficient drugs.

• DFG Programme: Research Grants