Modeling Small Molecule‐RNA Interactions: Applications to HIV TAR RNA

The purpose of this project is to design an improved or novel inhibitor of HIV TAR RNA, and, in doing so, to optimize 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 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 5.0 suite of programs are being optimized. Special attention will be paid to parameters that calculate electrostatics, including partial charges and solvation. To account for the flexibility of the structure, high levels of sampling of the receptor before the DOCK runs will be performed using replica exchange in 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 experimentally determined structures of TAR RNA. Once the computational procedures are successfully recreating the structural data set, a library of small molecule fragments designed to interact with RNA targets will be modeled and experimentally screened.