article · International Journal of Quantum Chemistry
Computational chemistry methods, specifically dispersion-corrected density functional theory and MP2, were applied to examine how the drug temozolomide interacts with guanine and its modified forms, 6-selenoguanine and 6-thioguanine, including a thiol tautomer. Across dozens of identified energy minima, the resulting heterodimers fall into three distinct structural categories: stacked arrangements with parallel aromatic systems, perpendicular configurations, and coplanar pairs bonded by hydrogen bonds. Dispersion forces act as the dominant attractive driver in stacked dimers, play a reduced role in perpendicular structures, and contribute least to coplanar formations. Substituting sulfur or selenium for oxygen causes little change in the overall geometry and energy profiles. However, tautomerisation in 6-thioguanine markedly alters the relative stability of the different configurations, reversing which geometries are most energetically favourable.
Temozolomide is an established chemotherapy agent, and understanding how it interacts at the molecular level with DNA bases and modified analogues helps reveal fundamental binding mechanisms. Mapping these interactions, including how chemical modifications and tautomeric shifts alter stability, offers insights into molecular recognition processes that underpin the behaviour of therapeutic compounds when targeting genetic material.
This work represents early-stage fundamental computational chemistry, clarifying molecular forces and structural arrangements between a therapeutic compound and nucleobase analogues. The findings could inform future computer-aided drug design and medicinal chemistry programmes targeting DNA interactions. However, the abstract does not indicate an immediate application pathway or direct commercial development, as the insights remain at the level of basic quantum chemical calculations.
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Temozolomide was paired with guanine, 6-selenoguanine, and 6-thioguanine, as well as the SH tautomer of the latter. The potential energy surface of each heterodimer was searched for all minima, using Dispersion-Corrected Density Functional Theory and MP2 methods. Among the dozens of minima, three categories were observed. Stacked geometries place the aromatic systems of the two molecules parallel to one another, while the two systems are roughly perpendicular to one another in a second category. Also found are coplanar structures held together by H-bonds. Dispersion proves to be a dominating attractive force for the stacked structures, less so for perpendicular, and smallest for the coplanar dimers. Geometries and energetics are relatively insensitive to S and Se substitution, but tautomerization reverses relative stabilities of different geometries.
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DOI: 10.1002/qua.25294
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