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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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