An extensive conformational analysis of 2´,3´-didehydro-2´,3´-dideoxythymidine (stavudine, d4T), a
nucleoside reverse transcriptase inhibitor widely used in anti-retroviral therapy, is presented. At 298.15 K all 19 allowed
d4T conformers are within the 5.51 kcal/mol Gibbs free energy range. Eight types of specific intramolecular interactions,
which govern the conformational properties of d4T, were identified, namely: O5΄H···O2, C1΄H···O2, C6H···O5΄,
C6H···O4΄, C5΄H1···O2, C5΄H2···O2, C6H···H1C5΄ and C2΄···O2. The results confirm the current point of view that the
biological activity of d4T is, most likely, connected with termination of the DNA chain synthesis in the 5´-3´ direction.
Thus, d4T competes with canonical thymidine for binding to the HIV-1 reverse transcriptase active site.
Keywords: 2´, 3´-didehydro-2´, 3´-dideoxythymidine, Biological activity, Conformational analysis, d4T, Density functional
theory, Electron density topological analysis, Electronic structure, Hydrogen bonds, NBO analysis, Nucleoside reverse
transcriptase inhibitor, NRTI, Stavudine
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