Ligand- (GRIND) and structure-based (GLUE/GRIND) 3D-QSAR approaches were compared for 55 (aryl-)bridged 2-aminobenzonitriles inhibiting HIV-1 reverse transcriptase (HIV-1 RT). The ligand-based model was built from conformers selected by in vacuo minimization. The available X-ray structure of 3v in complex with HIV-1 RT allowed comparative structure-based calculations using the new docking software GLUE for conformer selection. Both models were validated via statistics and via virtual receptor sites (VRS) considering pharmacophoric regions and mutual distances, which were also compared with experimental evidence. The statistics show slight superiority of the structure-based approach in terms of fitting and prediction. By encoding relevant molecular interaction fields (MIF) into pharmacophoric regions, 10 such regions were derived from both models; they all fit the real receptor except HBD2. Also mutual distances highly agree between the real site and both VRS. Although distances from the structure-based approach are closer to the real receptor, present data prove the validity of the ligand-based GRIND approach.