Extracellular inputs for GPCRs

Antonella di Pizio,

Leibniz Institute for Food Systems Biology, Technical University München, Germany

G protein-coupled odorant receptors: ligand discovery from structural models

With approximately 400 encoding genes in humans, odorant receptors are the largest subfamily of class A G-protein-coupled receptors (GPCRs). In 2001, trace amine-associated receptors (TAARs) were discovered as a new subfamily of class A GPCRs involved in odor detection and defined as non-canonical odorant receptors. A large repertoire of receptors is therefore required to mediate the signaling of odorant inputs. Despite its high relevance and representation, the odor-GPCRome is structurally poorly characterized: no experimental structures are available and the receptive range of most odorant receptors is unknown. In this talk, I will discuss computational methods and protocols that are being used to model the 3D structure of odorant receptors and their interaction with odorant molecules, highlighting challenges and opportunities. I will then present the results of a virtual screening campaign that led to the discovery of novel TAAR5 antagonists, as an example of the potential of computational approaches to deorphanize GPCRs.

Pau Gorostiza, ​

Institute for bioengineering of Catalonia IBEC-ICREA-BIST-CIBER, Barcelona, Spain

Controlling GPCR activity with photoswitchable drugs: basic research and future therapies

Lisa den Hollander,

Leiden University, The Netherlands

Targeting CC chemokine receptor 2:

From insurmountable antagonists to affinity-based probes

In early drug discovery pharmaceutical companies optimize the properties of drug candidates for a given therapeutic target, focusing on standard pharmacological parameters of affinity, potency and intrinsic activity. Despite these intensive efforts, the success rate of a candidate drug moving to the pre-clinical development phase is disappointingly low.

We have recently focused on the chemokine receptor CCR2, which is a G protein-coupled receptor – an important family of drug targets. This receptor is primarily activated by the endogenous chemokine CCL2. Several small molecule antagonists have been developed to inhibit this receptor, as it is involved in many diseases characterized by chronic inflammation. Unfortunately, all these antagonists lack clinical efficacy warranting a better understanding of their mechanism of action.

During this talk, I will show how our work on novel drug discovery concepts (e.g. target binding kinetics and allosteric modulation) and novel tools, such as an AfBP, contributes to this understanding, and how they open new avenues for CCR2, and GPCR small molecule drug discovery.

[1] Ortiz Zacarías NV et al. Design and Characterization of an Intracellular Covalent Ligand for CC Chemokine Receptor 2. J Med Chem. 2021, 64, 2608

[2] Zheng Y et al. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature. 2016, 540, 458

[3] Yang X et al. An Affinity-Based Probe for the Human Adenosine A2A Receptor. J Med Chem. 2018, 61, 7892