Three-dimensional RNA structure-based drug discovery

Abstract We have initiated a program to develop promising drug candidate leads using a new drug discovery paradigm based on three-dimensional RNA-structure-based computational screening of about 200,000 commercially available compounds for binding to selected RNA targets. As our first endeavor, we are using the three-dimensional structure of portions of the HIV-1 genome. Candidate lead compounds we seek are water-soluble, nonpeptide, nonnucleotide organic compounds generally with molecular weight less than 500 daltons. Structural studies of complexes formed with potential leads and their RNA targets should eventually yield insight into features governing affinity and specificity. The promising leads identified by virtual screening are tested for inhibition in functional assays. Leads will be selected for further development via computational and experimental combinatorial chemistry.