Crystal structures, absolute configurations and molecular docking studies of naftopidil enantiomers as α_1D-adrenoceptor antagonists

Chiral drug naftopidil (NAF), a specific α_1D-adrenoceptor (AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers showed the same antagonistic effects on the α_1D-AR, but the binding mechanism of these two stereochemical NAF isomers to the α_1D receptor remained unclear. Herein, we reported the crystallographic structures of optically pure NAF stereoisomers for the first time and unambiguously determined their absolute configurations. The crystal data of R and S enantiomers matched satisfactorily the pharmacophore model for α_1D-selective antagonists. Based on the constructed α_1D homology model, molecular docking studies shed light on the molecular mechanism of NAF enantiomers binding to α_1D-AR. The results indicated that NAF enantiomers exhibited the very similar binding poses and occupied the same binding pocket.