Conformational Landscape of the Nucleoside Reverse Transcriptase Inhibitor d4T: a Comprehensive Quantum-Chemical Approach

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.