Complexation between darunavir ethanolate and β-cyclodextrin

KOGAWA, A.C.; ZOPPI, A.; QUEVEDO, M.A.; LONGHI, M. R.; NUNES SALGADO, H.R.

Ribeirao Preto

Congreso; 9th International Congress of Pharmaceutical Sciences; 2013

INTRODUCTION. 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 β-cyclodextrin (βCD). 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 βCD. METHODS. Molecular modeling: DRV structure was subjected to conformational and energetic analyses using Gaussian03. DRV:βCD 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:βCD 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:βCD complex, with the moiety of DRV being buried into the βCD 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 βCD resonances were modified upon complexation. 2D ROESY assays showed correlations between internal βCD 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 βCD. KEYWORDS. darunavir ethanolate, β-cyclodextrin, complexation, molecular modeling, spectroscopic studies. REFERENCES 1. Fred.3.0.0 OpenEye Scientific Software, Santa Fe, NM http://www.eyesopen.com. 2. Omega.2.4.3 OpenEye Scientific Software, Santa Fe, NM http://www.eyesopen.com.