Molecular modeling of SWR-0342SA, a β3-selective agonist, with β1- and β3-adrenoceptor

The molecular dynamics (MD) simulations study in the formation of the complex between compound SWR-0342SA and β-ARs suggested that upon binding SWR-0342SA stimulates receptor activation through residues network (Asp104, Leu335 in β1-AR; Asp117, Ser209, Leu303, Ser191 in β3-AR) in an active conformation state. The models suggest that the structural origin of the selectivity of SWR-0342SA to β3-AR vs. β1-AR comes from the following results: (a) the tight interaction between the agonist and the TMs 3, 5, 6 and 2 nd EC loop. Asp117 interacts with the cationic amino group of the agonist molecule. (b) Additional contacts are done with Ser209, Leu303 and Ser191. These results are in good agreement with the binding affinities (pKi values) of SWR-0342SA to β-AR family expressed in recombinant mammalian cells.