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Chemical reactivity analysis of deoxyribonucleosides and deoxyribonucleoside analogues (NRTIs): a first-principles density functional approach

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Abstract

The structures, energetics, as well as several important chemical parameters, of antiretroviral drugs - nucleoside reverse transcriptase inhibitors (NRTIs) - and natural deoxyribonucleosides in both neutral, and positively and negatively charged states, are investigated. These studies are carried out within the frame work of first-principles density-functional theory (DFT), using the Becke-Lee-Yang-Parr (BLYP) generalized gradient corrections to the local spin density approximation exchange and correlation energy, norm-conserving pseudopotentials and a plane-wave expansion of Kohn-Sham orbitals. Conceptual DFT is used to determine global and local chemical reactivity parameters. Our results are in good agreement with the best available experiments to date. The variation in the bond lengths and bond angles on cation formation indicates that the electron is lost from the base part of these molecules. Further, the presence of the deoxyribose sugar moiety lowers their ionization potential and increases their electron affinity, in comparison to the isolated DNA base. The effectiveness of the drug action in terminating the viral DNA chain, is explained using the global reactivity parameters, by comparing the reactivities of the drug molecules with those of the competing deoxyribonucleosides. The widely followed clinical practice, of avoiding the simultaneous administration of certain drugs, is also explained from the hardness and softness parameters. For most of the drug molecules, our study validates the generally accepted wisdom, that monophosphorylation is the crucial reaction step in the phosphorylation reaction in DNA nucleotide synthesis.

Monophosphorylation of the drug molecule/corresponding deoxyribonucleoside in DNA nucleotide synthesis.

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Acknowledgements

This work was supported by DAE-BRNS grant (sanction no. 2010/37C/58/BRNS) and was possible due to the facilities, and help from the staff, of the BARC-Mumbai and IUAC-New Delhi computer centre.

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Authors and Affiliations

  1. Department of Chemistry, J. V. College, Baraut, Uttar Pradesh, 250611, India

    Vipin Kumar & Shyam Kishor

  2. High Pressure and Synchrotron Radiation Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India

    Lavanya M. Ramaniah

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  1. Vipin Kumar
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Correspondence to Vipin Kumar.

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Kumar, V., Kishor, S. & Ramaniah, L.M. Chemical reactivity analysis of deoxyribonucleosides and deoxyribonucleoside analogues (NRTIs): a first-principles density functional approach. J Mol Model 18, 3969–3980 (2012). https://doi.org/10.1007/s00894-012-1391-6

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