First chemical feature-based pharmacophore modeling of potent retinoidal retinoic acid metabolism blocking agents (RAMBAs): Identification of novel RAMBA scaffolds

The first three-dimensional (3D) pharmacophore model was developed for potent retinoidal retinoic acid metabolism blocking agents (RAMBAs) with IC50 values ranging from 0.0009 to 5.84 nM. The seven common chemical features in these RAMBAs as deduced by the Catalyst/HipHop program include five hydrophobic groups (hydrophobes), and two hydrogen bond acceptors. Using the pharmacophore model as a 3D search query against NCI and Maybridge conformational Catalyst formatted databases; we retrieved several compounds with different structures (scaffolds) as hits. Twenty-one retrieved hits were tested for RAMBA activity at 100 nM concentration. The most potent of these compounds, NCI10308597 and HTS01914 showed inhibitory potencies less (54.7% and 53.2%, respectively, at 100 nM) than those of our best previously reported RAMBAs VN/12-1 and VN/14-1 (90% and 86%, respectively, at 100 nM). Docking studies using a CYP26A1 homology model revealed that our most potent RAMBAs showed similar binding to the one observed for a series of RAMBAs reported previously by others. Our data shows the potential of our pharmacophore model in identifying structurally diverse and potent RAMBAs. Further refinement of the model and searches of other robust databases is currently in progress with a view to identifying and optimizing new leads.

Graphical abstractUsing the first chemical feature-based pharmacophore modeling of our retinoidal RAMBAs, we have identified novel RAMBAs with new scaffolds.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Developed first three-dimensional (3D) pharmacophore model for retinoidal RAMBAs. ► Model used to search databases that yielded novel RAMBAs with different scaffolds. ► Docking studies using CYP26A1 homology model revealed similar binding mode to know RAMBAs. ► Utilized our novel model to identify structurally diverse and potent RAMBAs.