CONICET | Buscador de Institutos y Recursos Humanos

Darunavir (DRV) is a protease inhibitor used in the treatment of AIDS. Unfortunately, DRV has low water solubility and poor bioavailability. A commonly applied approach to increase the solubility of drugs is the formation of complexes with â-cyclodextrin (âCD). In this context, the objective of this work was to evaluate, by theoretical and experimental approaches, the possibility of obtaining an inclusion complex between DRV and âCD. METHODS. Molecular modeling: DRV structure was subjected to conformational and energetic analyses using Gaussian03. DRV:âCD complexes were predicted by molecular docking, using software designed by Open Eye Inc (FRED, OMEGA),1,2 while molecular dynamics (MD) simulations were performed using Amber12. Experimental studies: DRV:âCD interactions were studied by nuclear magnetic resonance on a Bruker® Avance II High Resolution Spectrometer (400.16 MHz). RESULTS. From docking studies we found three clusters of conformations for the DRV:âCD complex, with the moiety of DRV being buried into the âCD hydrophobic cavity as follows: cluster-a: hexahydrofuryl moiety; cluster-b: aminobenzene ring and cluster-c: sulphonamide moiety. From MD the most stable conformation was identified by analyzing the corresponding free energies of binding, with cluster-b being energetically favored (-26.46 Kcal/mol), and cluster-a and cluster-c exhibiting lower predicted affinities (-23.54 and -17.29 Kcal/mol, respectively). Theoretical results were compared with spectroscopic studies, by 1H NMR was evidenced that DRV and âCD resonances were modified upon complexation. 2D ROESY assays showed correlations between internal âCD protons and aromatic protons of DRV, which is in agreement with the inclusion mode described for cluster-b by MD. CONCLUSION. The combination of theoretical and experimental techniques confirmed the formation of an inclusion complex between DRV and âCD.