Abstract: The research on 1-[(2-hydroxyethoxy)methyl]6-(phenylthio)thymine(HEPT), as one of the most important reverse transcriptase(RT) inhibitors against human immunodeficiency virus(HIV), remains a hot issue these years. The complex models of a series of 6-napthylmethyl substituted HEPT analogues with HIV-1 RT have been obtained by employing molecular docking approach. Using the binding conformations of these HEPT analogues, self-consistent and highly predictive 3D-QSAR models have been developed by performing CoMFA and CoMSIA analysis, which further guide the design of new candidates in return. Mapping these models back to the topology of the active site of HIV-1 RT led to a better understanding of the vital inhibitor-HIV-1 RT interactions. Taking compound 13 and its β-isomer 24 as the representatives, the reasons for the activity difference of α-and β-series analogues were presented by employing ab initio molecular orbital theoretical method. The best resulting CoMFA and CoMSIA models had conventional r² values of 0.997 and 0.994, while their leave-one-out cross-validated q² values were 0.787 and 0.747, respectively, suggesting a good predictive ability of these two models. Our research results also suggested that CoMSIA model was somewhat equivalent to the COMFA one. These models offer insight into the structural requirements for the activity of HEPT analogues as promising inhibitors, since there is only speculative knowledge of the target.

Key words: HIV-1 reverse transcriptase inhibitor, HEPT analogues, Molecular docking, Comparative molecular field analysis(CoMFA), Comparative molecular similarity indices analysis(CoMSIA), Ab initio molecular orbital theory