Molecular Modeling and Reengineering of A3 Adenosine Receptors

摘要: The development of ligands for the A3 adenosine receptor (AR) has been directed mainly by traditional medicinal chemistry, but influence structure-based approaches is increasing. Rhodopsin-based homology modeling had used many years to obtain three-dimensional models A3AR, and different A3AR have published describing hypothetical interactions with known having chemical scaffolds. recently structure human A2AAR provides a new template GPCR modeling, however even use as other AR subtypes still imprecise. compared here are based on bovine rhodopsin, β2-adrenergic receptor, templates. sequence contains only one cysteine residue (Cys166) in second extracellular loop (EL2), which putatively forms conserved disulfide bridge respective residues TM3 (Cys83). Homology helpful providing structural hypotheses design ligands. Site-directed mutagenesis shows an important role ligand recognition specific TM3, TM6 TM7. approach neoceptors means reengineering given GPCR, such recognize chemically tailored agonist ligand, no longer native agonist. It can serve validate molecular model, establishing proximity functional groups pair neoceptor its complementary assuming that this pharmacologically orthogonal respect species. may also be useful mechanistic elucidation projected future gene therapy.