This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this project is to design an improved or novel inhibitor of HIV TAR RNA, and, in doing so, to optimize the theoretical techniques for screening libraries against RNA targets. TAR RNA is found at the 5'end of nascent messenger RNA in infected host cells. At the beginning of the HIV life cycle, the protein Tat binds to TAR and facilitates HIV transcription. Because interruption of this interaction has been shown to prevent further HIV transcription, and thus replication, this complex has been identified as a potential drug target. As a class, RNA presents a difficult computational challenge as compared to proteins due to its electrostatic density and flexibility. In order to screen against RNA targets, the critical variables of the DOCK 5 suite of programs are being optimized. Special attention will be paid to parameters that calculate electrostatics, including partial charges, the scoring function, and solvation. TO account for the flexibility of the structure, high levels of sampling of the receptor both before and during the DOCK runs will be performed using the AMBER molecular dynamics package. The procedure is being validated using two test sets--one comprised of a variety of experimentally determined RNA-ligand complexes and the other compounds with experimentally derived binding affinities against the TAR target. Once the computational procedures are successfully recreating the experimental data, a large library of small molecules will be screened in the hopes of identifying a novel compound that binds well to the TAR target.
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