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Parameterization of AZT—A widely used nucleoside inhibitor of HIV‐1 reverse transcriptase
Author(s) -
Carvalho Alexandra T. P.,
Fernandes Pedro A.,
Ramos Maria J.
Publication year - 2006
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.21192
Subject(s) - reverse transcriptase , nucleoside reverse transcriptase inhibitor , zidovudine , nucleoside , density functional theory , reverse transcriptase inhibitor , human immunodeficiency virus (hiv) , nucleoside analogue , chemistry , in vivo , virology , computational chemistry , stereochemistry , biology , biochemistry , rna , genetics , viral disease , gene
Seven nucleoside reverse transcriptase (RT) inhibitors are currently used in the clinical treatment of acquired immunodeficiency syndrome (AIDS). These substrate analogues block DNA synthesis by the viral enzyme RT. However, the emergence of resistant variants of RT allied to their long‐term toxicity requires the design of new and better RT inhibitors, with long‐term in vivo efficacy. In this work we used density functional theory (DFT) calculations to develop a set of molecular mechanics (MM) parameters committed to the AMBER force field for one of the most used in the clinic nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine (AZT). These parameters were tested by comparing the optimized geometries of AZT at both the DFT and MM levels of theory. The ability of the new parameters to reproduce the torsional energy of the azide group was also verified by scanning the surface in MM with the new parameters and comparing the results with the same potential energy surface (PES) at the DFT level. Finally, the parameters were validated through classical MD simulations of AZT in aqueous environment. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007