Abstract
Single chemical entities with potential to simultaneously interact with two binding sites are emerging strategies in medicinal chemistry. We have designed, synthesized and functionally characterized the first bitopic ligands for the CB2 receptor. These compounds selectively target CB2 versus CB1 receptors. Their binding mode was studied by molecular dynamic simulations and site‐directed mutagenesis.
Highlights
G protein-coupled receptors (GPCRs) regulate a vast amount of cellular processes,[1] they form one of the most important pharmaceutical drug-target class (475 drugs in the market that represent 34% of all drugs approved by the US Food and Drug Administration).[2]
The design of bitopic ligands requires the selection of a moiety able to bind the orthosteric site
It is needed to develop a second pharmacophore unit for the vestibule or exosite. This is challenging because this additional cavity has not been properly characterized yet for most GPCRs
Summary
G protein-coupled receptors (GPCRs) regulate a vast amount of cellular processes,[1] they form one of the most important pharmaceutical drug-target class (475 drugs in the market that represent 34% of all drugs approved by the US Food and Drug Administration).[2]. While most GPCRs recognize polar ligands, GPCRs for lipid mediators are activated by hormone-like signaling molecules derived from lipid species, which possess long hydrophobic moieties This subfamily is mostly composed of the sphingosine-1-phosphate (S1P), lysophosphatidic acid (LPA) and cannabinoid (CB1R and CB2R) receptors.[16] In the crystal structures of these receptors[17] the extracellular N-terminus and extracellular loop 2 folds over the ligand binding pocket blocking the access to the orthosteric binding cavity from the extracellular environment. We have selected CB2R, instead of CB1R, due to its lack of adverse psychotropic effects along with its wide therapeutic application in pathologies such as cancer, neuroinflammation and pain.[20] Bivalent ligands have already been published for CB1R21–23 and CB2R.24 All these ligands were reported before the release of crystal structures, their binding characteristics remain unclear.[25,26] Here, we have used the recently released structure of CB2R in its active[27] Gi-bound conformation to identify the binding mode of the designed ligands Bivalent ligands have already been published for CB1R21–23 and CB2R.24 All these ligands were reported before the release of crystal structures, their binding characteristics remain unclear.[25,26] Here, we have used the recently released structure of CB2R in its active[27] Gi-bound conformation to identify the binding mode of the designed ligands
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