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，针对两种核苷类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）的构象空间开展了全面的量子化学研究。在T=298.15K条件下，研究发现d4A可在5.17千卡/摩尔的吉布斯自由能范围内形成21种构象异构体，而d4G在6.23千卡/摩尔范围内拥有20种构象异构体。两种核苷均由复杂的特异性非共价相互作用网络所稳定，包括常规（OHO、NHO型）和弱（CHO、CHN型）氢键，以及双氢（CHHC型）相互作用。针对OHO、NHO及CHO型氢键的自然键轨道（Natural Bond Orbital，NBO）分析表明，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型相互作用，电子密度从糖残基CH基团对应的反键轨道，转移至核碱基中对应同一基团的成键轨道。本研究结果验证了当前共识：d4A与d4G的生物活性与其在5′–3′方向终止DNA链合成密切相关，因此这类核苷可作为竞争性HIV-1逆转录酶抑制剂。