Conformational analysis of the anti-HIV Nikavir prodrug: comparisons with AZT and Thymidine, and establishment of structure–activity relationships/tendencies in other 6′-derivatives

Abstract

A comprehensive theoretical conformational analysis of the anti-HIV Nikavir prodrug was carried out; this prodrug has noticeable advantage over the approved drug AZT. The whole conformational parameters (χ, α, β, γ, δ, ϕ, P and ν_max) were analysed as well as the NBO natural atomic charges. The calculations were carried out by means of DFT/B3LYP and ab initio MP2 methods with full relaxation of all geometrical parameters. The search located at least 67 stable structures, 4 of which were within a 1 kcal/mol electronic energy range of the global minimum. By MP2 it corresponds to the calculated values of the exocyclic torsional angles χ = –108.0°, β = 14.5°, γ = 76.7° and ε = 71.5°. The results obtained are in accordance to those found in related anti-HIV nucleoside analogues. Comparisons of the conformers with those determined in the common anti-HIV drug AZT were carried out. A detailed analysis of the lowest vibrations (<200 cm⁻¹) in the best conformer of Nikavir was carried out. The most stable hydrated cluster of this conformer with 20 explicit water molecules was determined.

Calculations in five of its 6′-derivatives were performed to identify structural trends that might correlate with the anti-HIV activity of these compounds. Ten structure–activity relationships/tendencies were established that can help for the design of new drugs. Several recommendations for this design were expressed.

Keywords:

• Nikavir
• phosphazide
• AZT
• anti-HIV
• AIDS
• antiviral agents
• reverse transcriptase inhibitors
• DFT and MP2 methods

Acknowledgements

The authors wish to thank to the MCI through CTQ2010-18564 (subprogram BQU).