A novel heuristic of rigid docking scores positively correlates with full-length nuclear receptor LRH-1 regulation.

The nuclear receptor Liver Receptor Homolog-1 (LRH-1, NR5A2) is a ligand-regulated transcription factor and validated drug target for several human diseases. LRH-1 activation is regulated by small molecule ligands, which bind to the ligand binding domain (LBD) within the full-length LRH-1. We recently identified 57 compounds that bind LRH-1, and unexpectedly found these compounds regulated either the isolated LBD, or the full-length LRH-1 in cells, with little overlap. Here, we correlated compound binding energy from a single rigid-body scoring function with full-length LRH-1 activity in cells. Although docking scores of the 57 hit compounds did not correlate with LRH-1 regulation in wet lab assays, a subset of the compounds had large differences in binding energy docked to the isolated LBD vs. full-length LRH-1, which we used to empirically derive a new metric of the docking scores we call "{Delta}{Delta}G". Initial regressions, correlations and contingency analyses all suggest compounds with high {Delta}{Delta}G values more frequently regulated LRH-1 in wet lab assays. We then docked all 57 compounds to 18 crystal structures of LRH-1 to obtain averaged {Delta}{Delta}G values, which robustly and reproducibly associated with full-length LRH-1 activity in cells. Network analyses on the 18 crystal structures of LRH-1 suggest unique communication paths exist between the subsets of LRH-1 crystal structures that produced high vs. low {Delta}{Delta}G values, identifying a structural relationship between {Delta}{Delta}G and the position of Helix 6, a previously established regulatory helix important for LRH-1 regulation. Together, these data suggest computational docking can be used to quickly calculate {Delta}{Delta}G, which positively correlated with the ability of these 57 hit compounds to regulate full-length LRH-1 in cell-based assays. We propose {Delta}{Delta}G as a novel computational tool that can be applied to LRH-1 drug screens to prioritize compounds for secondary screening. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/592617v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1e3a780org.highwire.dtl.DTLVardef@109fcdcorg.highwire.dtl.DTLVardef@b80fa6org.highwire.dtl.DTLVardef@b68fe_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO C_FIG