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 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.

Effect of the sulfur atom on S2 and S4 positions of the uracil ring in different DNA:RNA hybrid microhelixes with three nucleotide base pairs

“…In general, DFT methods appear as the most suitable today because they offer a compromise between the important demands put on computer power and time, and the desired chemical accuracy. Furthermore, these methods have been used satisfactorily in many spectroscopic studies, in nucleosides, DNA base pairs, water cluster of nucleobases, biological molecules, and in drug designing, in particular the M062X method selected here …”

“…Several parameters characterize the conformation of a nucleotide, namely the orientation of the purine/pyrimidine base unit regarding the furanose sugar unit (SU), the conformation of SU, and the orientation of the phosphate unit with reference to SU. Following the Saenger's notation, the atomic description of a nucleotide as well as the main endocyclic and exocyclic torsional angles appears as described in Scheme .…”

Quantum-mechanical survey of the novel conformational and tautomeric transformations of the classical Watson-Crick А·Т(WC), reverse Watson-Crick А·Т(rWC), Hoogsteen А·Т(Н) and reverse Hoogsteen А·Т(rН) DNA base pairs

“…Applied level of theory has successfully proved itself for the calculations of the similar systems [38]- [41]. A scaling factor that is equal to 0.9668 [42]- [45] has been applied in the present work for the correction of the harmonic frequencies of all conformers and TSs of their conformational transitions. We have confirmed the local minima and TSs, localized by Synchronous Transitguided Quasi-Newton method [46], on the potential energy landscape by the absence or presence, respectively, of the imaginary frequency in the vibrational spectra of the complexes.…”

Structure and conformational analysis of the anti-HIV reverse transcriptase inhibitor AZT using MP2 and DFT methods. Differences with the natural nucleoside thymidine. Simulation of the 1st phosphorylation step with ATP

“…Thus, this task was undertaken in a similar way to that carried out in several NSs 19,92,93 and NDs, 44,94 but including in this case the M06-L and M05-2X methods, i.e. A full conformational study of this molecule has not been reported yet.…”