Conformational analysis of the anti-HIV Nikavir prodrug: comparisons with AZT and Thymidine, and establishment of structure-activity relationships/tendencies in other 6'-derivatives.
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 νmax) 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.
a Facultad de Ciencias Químicas, Departamento de Química-Física I, Universidad Complutense, Ciudad Universitaria , Madrid 28040 , Spain.
Ahmed A
AA
El-Sayed
A
A
Tamara Molina
M C
MC
Álvarez-Ros
M
M
Alcolea Palafox
D019380:Anti-HIV Agents / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D063065:Organophosphonates / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry; D011789:Quantum Theory; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013936:Thymidine / Q000737:chemistry*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000737:chemistry*
C000604073:3'-azido-2',3'-dideoxythymidine 5'-H-phoshonate; D019380:Anti-HIV Agents; D063065:Organophosphonates; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D013936:Thymidine
AIDS; AZT; DFT and MP2 methods; Nikavir; anti-HIV; antiviral agents; phosphazide; reverse transcriptase inhibitors