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 <i>T</i> = 298.15 K. Both nucleosides are shaped by a sophisticated network of specific noncovalent interactions, including conventional (OHO, NHO) and weak (CHO, CHN) hydrogen bonds, as well as dihydrogen (CHHC) contacts. For the OHO, NHO, and CHO hydrogen bonds, natural bond orbital analysis revealed hyperconjugative interactions between the oxygen lone pairs and the antibonding orbital of the donor group. For the CHHC 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.

本研究在MP2/6-311++G(d,p)//B3LYP/6-31G(d,p)理论级别下，对两种核苷类HIV-1逆转录酶抑制剂——2′,3′-二脱氢-2′,3′-二脱氧腺苷（2′,3′-didehydro-2′,3′-dideoxyadenosine，d4A）与2′,3′-二脱氢-2′,3′-二脱氧鸟苷（2′,3′-didehydro-2′,3′-dideoxyguanosine，d4G）的构象势能面开展了全面的量子化学研究。研究发现，在温度T=298.15 K时，d4A可在5.17 kcal/mol的吉布斯自由能区间内形成21种构象体，而d4G则可在6.23 kcal/mol的区间内形成20种构象体。两种核苷的空间构型均由复杂的特异性非共价相互作用网络维系，包括常规（OHO、NHO型）与弱（CHO、CHN型）氢键，以及二氢键（CHHC型）相互作用。针对OHO、NHO及CHO型氢键，自然键轨道（natural bond orbital）分析揭示，氧原子孤对电子与给体基团的反键轨道之间存在超共轭相互作用；对于CHHC型二氢键，电子密度由糖残基CH基团对应的反键轨道，迁移至核碱基中对应基团的成键轨道。本研究结果验证了现有学术认知：d4A与d4G的生物活性与其在5′→3′方向上终止DNA链合成密切相关，因此这两种核苷可作为竞争性HIV-1逆转录酶抑制剂发挥作用。