Structural and energetic properties of the potential HIV-1 reverse transcriptase inhibitors d4A and d4G: a comprehensive theoretical investigation

A comprehensive quantum-chemical investigation of the conformational landscapes of two nucleoside HIV-1 Reverse Transcriptase inhibitors, 2',3'-didehydro-2',3'-dideoxyadenosine (d4A), and 2',3'-didehydro-2',3'-dideoxyguanosine (d4G), has been performed at the MP2/6-311++G(d,p)//B3LYP/6-31G(d,p) level of theory. It was found that d4A can adopt 21 conformers within a 5.17 kcal/mol Gibbs free energy range, whereas d4G has 20 conformers within 6.23 kcal/mol at T = 298.15 K. Both nucleosides are shaped by a sophisticated network of specific noncovalent interactions, including conventional (OH[Formula: see text]O, NH[Formula: see text]O) and weak (CH[Formula: see text]O, CH[Formula: see text]N) hydrogen bonds, as well as dihydrogen (CH[Formula: see text]HC) contacts. For the OH[Formula: see text]O, NH[Formula: see text]O, and CH[Formula: see text]O hydrogen bonds, natural bond orbital analysis revealed hyperconjugative interactions between the oxygen lone pairs and the antibonding orbital of the donor group. For the CH[Formula: see text]HC contacts, the electron density migrates from the antibonding orbital, corresponding to the CH group of the sugar residue, to the bonding orbital relative to the same group in the nucleobase. The results confirm the current belief that the biological activity of d4A and d4G is connected with the termination of the DNA chain synthesis in the 5'-3' direction. Thus, these nucleosides act as competitive HIV-1 Reverse Transcriptase inhibitors.