Conformational analysis, molecular structure and solid state simulation of the antiviral drug acyclovir (zovirax) using density functional theory methods

Abstract

The five tautomers of the drug acyclovir (ACV) were determined and optimised at the MP2 and B3LYP quantum chemical levels of theory. The stability of the tautomers was correlated with different parameters. On the most stable tautomer N1 was carried out a comprehensive conformational analysis, and the whole conformational parameters (R, β, Φ, φ1, φ2, φ3, φ4, φ5) were studied as well as the NBO Natural atomic charges. The calculations were carried out with full relaxation of all geometrical parameters. The search located at least 78 stable structures within 8.5 kcal/mol electronic energy range of the global minimum, and classified in two groups according to the positive or negative value of the torsional angle j1. In the nitrogen atoms and in the O2' and O5' oxygen atoms of the most stable conformer appear a higher reactivity than in the natural nucleoside deoxyguanosine. The solid state was simulated through a dimer and tetramer forms and the structural parameters were compared with the X-ray crystal data available. Several general conclusions were emphasized.

Figure 1

Molecular structure and definition of the torsional angles in tautomer N1 of acyclovir.

Figure 2

Five tautomers described in acyclovir.

Figure 3

Relationship/tendency observed between the relative electronic energy ΔE + ZPE correction of the different tautomers vs. (a) the dipole moment μ. and (b) the exocyclic torsional angle φ₁.

Figure 4

Geometry of the six most optimum conformers selected for each rotation angle φ₁ determined in A1 conformer of N1 tautomer of acyclovir at B3LYP/6-31G(d,p) level. The values of the strongest intramolecular H-bonds are also included.

Figure 5

Natural atomic charges and optimum bond lengths in conformer B2 of tautomer N1 of acyclovir at B3LYP/6-31G(d,p) and MP2/6-31G(d,p) levels, in fuchsia and green colours, respectively.

Figure 6

Distribution of the 78 optimum stable calculated conformers at the B3LYP/6-31G(d,p) level in tautomer N1 of acyclovir according to their exocyclic torsional angle φ₁ and their: (a) relative electronic energy ΔE + ZPE correction; (b) relative Gibbs energy ΔG; and (c) the distance R. The most stable conformers of each type are pointed.

Figure 7

Distribution of the 78 optimum stable calculated conformers in tautomer N1 of acyclovir, according to the values of the exocyclic torsional angles: φ₂. φ₃. φ₄ and φ₅ versus the angle φ₁.

Figure 8

Distribution of the 78 optimum stable calculated conformers in tautomer N1 of acyclovir according to the values of the angles Φ and β, and the dipole moment μ versus the angle φ₁.

Figure 9

3D plots with the relative energies of the 78 optimum stable conformers according to the values of the exocyclic torsional angles: φ₁. φ₂. φ₃ and φ₄ versus relative electronic energy ΔE + ZPE.

Figure 10

The optimized dimer and tetramer forms in conformer A1 of acyclovir at the B3LYP/6-31G(d,p) level. The H-bonds observed are in Å and the E (RB+HF-LYP) in a. u.