Searching for a reliable orientation of ligands in their binding site: comparison between a structure-based (Glide) and a ligand-based (FIGO) approach in the case study of PDE4 inhibitors.

Two 3D QSAR Grid/Golpe models, differing in the alignment criterion of the studied phosphodiesterase 4 (PDE4) inhibitors, were compared. The docking-guided alignment, obtained by exploiting the known 3D structure of the PDE4, was used to test and validate the field-fit alignment solution proposed by FIGO procedure. The analysis of the direct (docking) and indirect (FIGO) superposition methodologies occurs through the comparison of the respective PLS coefficient maps. The inclusion in the FIGO algorithm of factors related to the hydrophobicity and shape of the molecules leads to promising results, making the new FIGO algorithm a valid alternative in the molecule overlay, particularly when the 3D structure of the target is unknown.