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Updated: May 23, 2026

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Complete conformational space of the potential HIV-1 reverse transcriptase inhibitors d4U and d4C. A quantum chemical
Alla G Ponomareva1, Yevgen P Yurenko, Roman O Zhurakivsky
1Laboratory of Computational Structural Biology, Institute of Molecular Biology and Genetics, NAS of Ukraine, Akademika Zabolotnoho Street 150, 03143 Kyiv, Ukraine.
Abstract:
A comprehensive quantum-chemical conformational analysis of two nucleoside analogues, 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-didehydro-2',3'-dideoxycytidine (d4C), is reported. The electronic structure calculations were performed at the MP2/6-311++G(d,p)//B3LYP/6-31++G(d,p) level of theory. It was found that d4U and d4C adopt 20 conformers and 19 conformers, respectively, which correspond to local minima on the respective potential energy landscapes. QTAIM and NBO analyses show that the d4U and d4C conformers are stabilised by a complicated network of specific intramolecular interactions, which includes conventional (OHO) and non-conventional (CHO, CHHC) H-bonds as well as closed-shell van der Waals (CO) contacts. A satisfactory linear correlation was found between Grunenberg's compliance constants for closed-shell intramolecular interactions and their energy. It is shown that there are no conformational obstacles for incorporation of d4U and d4C into the double helical A and B forms of DNA. The less pronounced biological activity of d4U as compared to 2',3'-didehydro-2',3'-dideoxythymidine (d4T) is most likely due to the presence of the bulky methyl group at the 5-position of d4T, which can be recognised by target enzymes.
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