Interactions of Nucleic Acid Bases with Temozolomide. Stacked, Perpendicular, and Coplanar Heterodimers

Abstract

Temozolomide (TMZ) was paired with each of the five nucleic acid bases, and the potential energy surface searched for all minima, in the context of dispersion-corrected density functional theory and MP2 methods. Three types of arrangements were observed, with competitive stabilities. Coplanar H-bonding structures, reminiscent of Watson-Crick base pairs were typically the lowest in energy, albeit by a small amount. Also very stable were perpendicular arrangements that included one or more H-bonds. The two monomers were stacked approximately parallel to one another in the third category, some of which contained weak and distorted H-bonds. Dispersion was found to be a dominating attractive force, largest for the stacked structures, and smallest for the coplanar dimers.

Interactions between temozolomide and guanine and its S and Se-substituted analogues

“…Negative red sections are located around unprotonated N atoms, as well as the O/S/Se atoms. The corresponding MEP around TMZ was previously reported . This MEP in Figure exhibits primary negative potential around its two O atoms, with positive regions around its H atoms and directly above its six‐membered ring.…”

“…This situation brings up the question as to whether the dimers of this lower energy tautomer with TMZ are similarly more stable than those involving canonical guanine. This question can be answered by perusal of the values reported in parentheses in Table which list the energy of the indicated heterodimer with respect to the most stable complex between TMZ and the N 7 H tautomer of guanine, reported earlier . It is immediately clear from some of the negative values that despite its higher intrinsic energy, the canonical N 9 H tautomer forms heterodimers that are more stable than even the lowest energy dimer of N 7 H guanine.…”

“…This question can be answered by perusal of the values reported in parentheses in Table 1 which list the energy of the indicated heterodimer with respect to the most stable complex between TMZ and the N 7 H tautomer of guanine, reported earlier. [35] It is immediately clear from some of the negative values that despite its higher intrinsic energy, the canonical N 9 H tautomer forms heterodimers that are more stable than even the lowest energy dimer of N 7 H guanine. Note that this reversal is true not only of the most stable G1 dimer, but of G2 and G3 as well, and extends over a full range of levels of theory.…”

“…[82,83] For that reason, the molecular electrostatic potentials (MEPs) of the molecules of interest are presented in Figure 4, reported. [29][30][31][32][33][34][35] This MEP in Figure 4 exhibits primary negative potential around its two O atoms, with positive regions around its H atoms and directly above its six-membered ring.…”

“…Using the lessons learned, work progressed to larger pharmacological agents chloroquine and quercetin, as well as possible homodimers of TMZ . Progressing toward other aspects of biological activity, the interaction of TMZ with each of the nucleic acid bases was examined and demonstrated the possibility of binding much like the standard Watson‐Crick pairing that is instrumental to the structure and function of DNA . But at the same time, quite different sorts of geometries, energetically similar to or even more stable than such pairing were revealed for the first time.…”