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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
ABSTRACT - Internet Electron. J. Mol. Des. February 2004, Volume 3, Number 2, 73-82

Electronic Structure of Some Antiviral Compounds
Madalin G. Giambasu, Carmen C. Diaconu, and Mihaela Hillebrand
Internet Electron. J. Mol. Des. 2004, 3, 73-82

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Abstract:
As a first step in a theoretical approach on the multidrug resistance (MDR) process occurring during long-time therapy with antiviral and antitumoral drugs and the molecular modeling of the interaction of the drugs with the P-Glycoprotein (P-gp) overexpressed in these cases, we have investigated the electronic structure of some antiviral compounds, Zidovudine (AZT, 1), 3'-azido-3'-deoxy-5'-O-oxalylthymidine acid (AZT-Ac, 2), 3'-azido-3'-deoxy-5'-O-oxalyl-N-valinethymidine (AZT-Val, 3) and 3'-azido-3'-deoxy-5'-O-iso-nicotinoyl-thymidine (AZT-Iso, 4). The calculations were performed by semiempirical, AM1, and ab initio 6-31G* methods using the AMSOL and GAMESS programs. A conformational search considering the most significant torsions was previously made using the Hyperchem program and the lowest energy conformers were further subject to a fully optimization in octanol, model for a nonpolar solvent and water. To establish the position of the azide group in respect with the ribose cycle, the potential energy surface was built, considering as coordinate the torsion about the ribose-azide bond. The solvation effects in the ab initio method were treated in the frame of the selfconsistent reaction field (SCRF). For all the compounds, the conformational search revealed similar relative positions of the thymine and ribose ring, slightly influenced by the solvent. Concerning the azide group the semiempirical results were drastically changed in going from in vacuo to water optimizations. A strongly stabilized solvated species, with a different charge distribution than in vacuo was evidenced in water. The calculated free energies of solvation are larger in water in comparison with octanol, excepting compound 3 for which the difference is small in agreement with its larger expected lipophilicity. The solvation effects predicted by the ab initio method are smaller. The essential change in the electronic charge distribution of the azide nitrogens in water in comparison to in vacuo calculations shows that in order to have a correct estimation of the electrostatic contributions in the modeling of protein-AZT derivatives interaction the solvation processes must be taken into account.

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