Molecular Modeling Of APOBEC3G/F-Vif Complex And Its Implication In Virtual Screening For Anti-HIV-1Drugs

The host restriction factors APOBEC3G/F (A3G/F)are cytidine deaminases that incorporate into HIV-1virions and efficiently inhibit viral replication. The HIV-1encoding the viral infectivity factor(Vif) binds to A3G/F and induces its degradation, thereby counteracting the antiviral activity of A3G/F. Thus, blocking the interaction of A3G/F-Vif, which impedes Vif-mediated degradation and allows A3G/F efficiently inhibit the replication of HIV-1, becomes an attractive strategy for anti-HIV drug development. There is no full-length3D structure of A3G, A3F and Vif solved by X-ray or nuclear magnetic resonance(NMR), which sets a limit tothe development of novel anti-HIV-1drugs. However. molecular modeling can effectively solve this problem. The models of A3G/F-Vif complexes and A3G-Dimer complex were constructed by molecular modeling. The determinants which affect the A3G/F-Vif interaction were predicted according to the built models. In addition to the reported crucial residues, our analyses reveal the motif124YYFW127of A3G plays an important role in the interaction with Vif and the A3F amino acids V287,L299,S322,E329,E373and291LARH294, which are essential for binding to Vif. The results of some biochemical test validated our prediction and hypothesis, which means high qualityof these models and good accuracyof the predictions.We alsoconducted a virtual screening of35,894lead-like compounds derived from NCI database to identify the inhibitors of the A3G-Vif interaction. Combining with experimental approaches,we were able to identify four small compounds that bound directly to A3G, suppressed A3G from Vif-mediated degradation. Taken together, our results provide a promising ground for mechanism research of APOBEC3family and efficiently promote the development of novel anti-HIV-1drugs.