title: Design and implementation of an ribonucleic acid (RNA) directed fragment library.
abstract: The design of RNA binding ligands is complicated by issues of specificity, target flexibility, and the tractability of known RNA inhibitors toward chemical derivitization. To address these difficulties, an RNA-directed fragment compound library is presented. We began with an analysis of 120 small molecules with reported RNA-binding activity. Calculated physical and chemical properties for the RNA ligands are comparable to those of ligands for established protein drug targets. To ensure that our library contained RNA-binding functionalities that might not be detected by the above comparisons, 114 fragment compounds were purchased on the basis of similarity to substructures of RNA ligands. Five "hits" were identified for the decoding site from the bacterial ribosome by NMR. These included fragments derived from A-site binding ligands but also compounds not previously identified as A-site binders. Hits generated in this manner can be used to probe the interaction surface of RNA and its conformational plasticity, facilitating structure-based optimization.
authors.affiliation: Department of Physics, University of Jordan, Amman 11942, Jordan.
authors.forename: Khaled
authors.initials: K
authors.lastname: Bodoor
authors.forename: Vamsi
authors.initials: V
authors.lastname: Boyapati
authors.forename: Vikram
authors.initials: V
authors.lastname: Gopu
authors.forename: Marietta
authors.initials: M
authors.lastname: Boisdore
authors.forename: Kiran
authors.initials: K
authors.lastname: Allam
authors.forename: Janae
authors.initials: J
authors.lastname: Miller
authors.forename: W Dale
authors.initials: WD
authors.lastname: Treleaven
authors.forename: Thomas
authors.initials: T
authors.lastname: Weldeghiorghis
authors.forename: Fareed
authors.initials: F
authors.lastname: Aboul-ela
mesh_terms: D001665:Binding Sites; D002627:Chemistry, Physical; D016208:Databases, Factual; D015195:Drug Design; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008970:Molecular Weight; D009930:Organic Chemicals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011786:Quality Control; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D008024:Ligands; D009930:Organic Chemicals; D054852:Small Molecule Libraries; D012313:RNA