Nucleoside analogues (anti-herpes drug) are widely used to combat the Herpes Simplex Virus (HSV). In recent years, there have been efforts to explain the properties and action even of biomolecules, using an accurate first-principles methodology. In this paper, we have studied the properties and successfully explained the effectiveness of anti-herpes drug. Working within the framework of firstprinciples density functional theory (DFT) using the B3LYP functional and the 6-311?G(d,p) basis set, the structural, electronic properties and thermochemistry of hydrolysis and displacement reactions were determined. Conceptual DFT was used to determine global and local descriptors and intermolecular charge transfer. By comparing the reactivities of the drugs with those of the competing natural nucleoside (dG) during monophosphorylation we show that, as is commonly believed the drugs act by terminating the viral DNA chain.