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Nucleic Acid Structure-Based Ligand Discovery
 
  We have been developing a strategy to discover novel ligands based on detailed three-dimensional RNA structure. While there has been much effort to design diagnostic and therapeutic agents that bind to protein receptors based on their three-dimensional structure, there has been little or no effort to design drugs rationally on the basis of the sequence-dependent three-dimensional structure of DNA or RNA. Key to our successful development of this virtual screening methodology has been establishment of an empirical binding free energy function. The first target selected for application was HIV-1 TAR RNA. Binding of the Tat protein to TAR RNA is necessary for viral replication of HIV-1. The methodology developed for virtual screening was utilized to identify potential inhibitors (nonpeptide and nonnucleotide) of the Tat-TAR interaction. Screening of the Available Chemicals Directory (ACD) yielded a ranked list of 500 compounds. We purchased 43 and assayed them experimentally. Of these, eight inhibited the Tat-TAR interaction at 100 nM concentration and three more at 1 micromolar. Some of these compounds also inhibited Tat transactivation in a cell-based assay. NMR was used to determine the structure of one of these ligands complexed to TAR, which explained well why the ligand bound so tightly. Current research entails experimental as well as computational studies to improve the ligands that bind to TAR as well as identifying and improving those that bind to other RNA targets.