Modeling of HIV-1 TAR RNA-Ligand Complexes

Trans activation response (TAR) region is an RNA target of considerable importance in controlling the replication cycle of the human immunodeficiency virus (HIV). At a transcriptional level, HIV-1 is regulated by means of the interaction between Tat protein and TAR RNA. The TAR-Tat complex is an attractive target for developing novel antiviral drugs. Herein, the recognition modes of 8 structurally different ligands, as mimics of Tat protein, in complex with a TAR RNA are investigated using the DOCK 6.4 flexible docking protocol in association with the newly-implemented scoring function AMBER including solvation implicitly through the generalized Born solvent-accessible surface area (GB/SA) continuum model. The TAR RNA-ligand interactions are further characterized and contrasted using the nature of separate contributions to the stability of the complexes. Several interesting implications for the key challenge, the development of low molecular weight ligands binding to HIV-1 TAR RNA with high affinity and specificity, are discussed.