First-principles DFT study of some acyclic nucleoside analogues (anti-herpes drugs)
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Med Chem Res DOI 10.1007/s00044-013-0587-3
ORIGINAL RESEARCH
First-principles DFT study of some acyclic nucleoside analogues (anti-herpes drugs) Vipin Kumar • Shyam Kishor • Lavanya M. Ramaniah
Received: 5 January 2013 / Accepted: 28 March 2013 Ó Springer Science+Business Media New York 2013
Abstract 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. Keywords Density functional theory Ab initio calculations Anti-herpes Chemical reactivity descriptors Hydrolysis
Electronic supplementary material The online version of this article (doi:10.1007/s00044-013-0587-3) contains supplementary material, which is available to authorized users. V. Kumar (&) S. Kishor Dept. of Chemistry, J. V. College, Baraut 250611, Uttar Pradesh, India e-mail: [email protected] L. M. Ramaniah High Pressure and Synchrotron Radiation Physics Divison, Physics Group, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
Introduction Herpes is the most common and contagious viral infection in humans caused by the Herpes Simplex Virus (HSV). It was amongst the first diseases to be treated by means of nucleoside analogues (Weber and Cinatl, 1996), which include acyclic Guanine analogues Aciclovir, Ganciclovir and Penciclovir. These analogues have prodrugs Valaciclovir, Valganciclovir and Famciclovir, respectively. Most of the nucleoside analogues exhibit their antiviral activity by terminating elongation of the nucleic acid chain during DNA (viral) synthesis. In the cell, the virus uses the natural nucleoside of the cell and its machinery to make additional viral DNA. When analogues (drugs) are present, they compete with the natural nucleosides [such as deoxyguanosine (dG)] in the viral DNA polymerization reaction (which occurs in two steps, phosphorylation followed by incorporation into the growing DNA strand). During phosphorylation the analogues are converted to triphosphate metabolites by viral and/or cellular enzymes. Among the three steps of phosphorylation, the viral enzyme [Thymidine Kinase (TK)]-induced first step (monophosphorylation) is crucial for the specific (and selective) activity of the drugs (Clercq and Neyts, 2009). The monophosphorylated metabolit
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