Successful in silico discovery of novel nonsteroidal ligands for human sex hormone binding globulin.

Using "in silico" drug design methodologies, we have discovered several nonsteroidal compounds of natural origin that bind to human sex hormone binding globulin (SHBG) with affinity constants of 0.1 x 10(6) to 1.2 x 10(6) M(-1). The computational solutions we developed involved pharmacophore-aided database search, virtual protein-ligand docking, and structure-activity modeling with "inductive" QSAR descriptors. By screening 23 836 natural substance structures, we identified 29 potential SHBG ligands, and eight of these bound the protein in vitro. These nonsteroidal ligands belong to four classes of molecular scaffolds with several available substitution positions that could allow chemical modification to enhance SHBG-binding activity. Interestingly, one of these compounds is structurally similar to a dicyclohexane derivative that binds to rat SHBG and causes azospermia when administered to male rats. Taken together, the in silico strategy we have developed will aid in the discovery of nonsteroidal ligands of SHBG with novel pharmacological properties.