| Abstract
| - Using “in silico” drug design methodologies, we have discovered several nonsteroidal compoundsof natural origin that bind to human sex hormone binding globulin (SHBG) with affinityconstants of 0.1 × 106 to 1.2 × 106 M-1. The computational solutions we developed involvedpharmacophore-aided database search, virtual protein−ligand docking, and structure−activitymodeling 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. Thesenonsteroidal ligands belong to four classes of molecular scaffolds with several availablesubstitution positions that could allow chemical modification to enhance SHBG-binding activity.Interestingly, one of these compounds is structurally similar to a dicyclohexane derivative thatbinds 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 ofSHBG with novel pharmacological properties.
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