Conformational analysis of fenoterol stereoisomers

Abstract

Fenoterol is a relatively long-acting selective agonist of β2 adrenergic receptor (β2-AR) used in the treatment of asthma. Its molecule contains two stereogenic centers, thus, the compound exists as four stereoisomers. The clinically used drug, rac-fenoterol, is a racemic mixture of (R,R)-fenoterol and (S,S)-fenoterol. Our previous research [3] indicated that fenoterol stereoisomers significantly differ in affinity, selectivity and functional activity with respect to β2-AR. Radioligand displacement studies indicated that (R,R)-isomer shows the strongest affinity and selectivity followed by (R,S)- and (S,R)-forms. Molecular modeling and docking simulations suggest that stereochemistry significantly influences the orientation of the molecule within the binding site and its internal conformation. Conformational search analysis of all four isomers was performed by monitoring the potential energy change with gradual rotation of each rotatable dihedral angle. Local minimum was selected for each dihedral and used to constructed optimized molecule. The molecule was further subjected to energy minimization and molecular dynamics simulations in vacuo and in water. The results allowed to define conformations representing the global minimum of energy for each stereoisomer. These conformations can be compared to the internal conformation of each stereoisomer in complex with β2-AR. Among stereoisomers, the conformation of (R,R)-fenoterol in complex with β2-AR shows the closest correspondence with the conformation obtained in molecular dynamics simulation in water. Thus, binding of (R,R)-isomer is additionally promoted by the lowest increase of internal energy associated with adopting the receptor-induced conformation upon binding.