ENERGETIC, CONFORMATIONAL AND ELECTRON DENSITY TOPOLOGICAL PROPERTIES
OF 2?,3?-DIDEHYDRO-2?,3?-DIDEOXYTHYMIDINE: A QUANTUM CHEMICAL STUDY
Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv;
Comprehensive conformational analysis of 2?,3?-didehydro-2?,3?-dideoxythymidine (d4T), also known as anti-AIDS drug stavudine, has been performed for the first time at the MP2/6-311++G(d,p)//DFT B3LYP/6-31++G(d,p) level of the theory. It was established that d4T energy landscape contained 19 local minima, which corresponded to stable conformers. Eight types of specific intramolecular interactions, which govern the d4T conformational properties, were identified, namely: O5?H???O2, C1?H????O2, C6H???O5?, C6H???O4?, C5?H1????O2, C5?H2????O2, C6H???H1?C5?, C2????O2. The obtained results confirm the actual point of view that d4T biological activity is, most likely, connected with termination of the DNA chain synthesis in the 5?-3? direction. Thus, d4T competes with canonical thymidine in binding an active site of HIV-1 reverse transcriptase.
Key words: 2?,3?-didehydro-2?,3?-dideoxythymidine, conformational analysis, hydrogen bonds, biological activity, electron density topological analysis, NBO analysis.
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