An updated steroid benchmark set and its application in the discovery of novel nanomolar ligands of sex hormone-binding globulin.

A benchmark data set of steroids with known affinity for sex hormone-binding globulin (SHBG) has been widely used to validate popular molecular field-based QSAR techniques. We have expanded the data set by adding a number of nonsteroidal SHBG ligands identified both from the literature and in our previous experimental studies. This updated molecular set has been used herein to develop 4D QSAR models based on "inductive" descriptors and to gain insight into the molecular basis of protein-ligand interactions. Molecular alignment was generated by means of docking active compounds into the active site of the SHBG. Surprisingly, the alignment of the benchmark steroids contradicted the classical ligand-based alignment utilized in previous CoMFA and CoMSIA models yet afforded models with higher statistical significance and predictive power. The resulting QSAR models combined with CoMFA and CoMSiA models as well as structure-based virtual screening allowed discovering several low-micromolar to nanomolar nonsteroidal inhibitors for human SHBG.