Exploring the structure–activity relationship of oxazolidinones as HIV-1 protease inhibitors—QSAR and pharmacophore modelling studies

• 2D, 3D QSAR and pharmacophore models were developed for oxazolidinone derivatives.
• Developed QSAR models were validated internally and externally.
• Electrostatic and steric descriptors significantly affect HIV-1 PI activity.
• Pharmacophore model indicates the significance of aromatic & hydrogen bond acceptor.

In the present study, 2D QSAR and 3D QSAR models and pharmacophore hypothesis were evaluated for a series of N-aryl-oxazolidinone-5-carboxamides to predict their HIV-1 protease inhibitory activity. The developed QSAR models were validated by external validation method, leave-one-out and leave-many-outcross validation, Y-randomization method and applicability domain analysis. The primary findings of this study were that the number of carbon atoms separated from any specific carbon atom by 2- and 7-bond distances, and the number of fluorine atoms separated from any specific fluorine atom by a 5-bond distance in a molecule, altered the compounds' inhibitory action on HIV-1 protease. Further, 3D QSAR study results indicated that the presence of electrostatic and steric field descriptors in N-aryl-oxazolidinone-5-carboxamides significantly inhibited HIV-1 protease. The generated pharmacophore hypothesis of the compounds indicated the significance of the two aromatic and three hydrogen bond acceptor features on HIV-1 protease's inhibitory activity. The proposed model also provided a better understanding of HIV-1 protease's inhibitory activity on oxazolidinones and could be used as guidance for the proposition of new anti-HIV agents.