title: Which aminoglycoside ring is most important for binding? A hydropathic analysis of gentamicin, paromomycin, and analogues.
abstract: The NMR structures of gentamicin and paromomycin in complex with the A-site of Escherichia coli 16S ribosomal RNA were modified with molecular modeling to 12 analogues. The intermolecular interactions between these molecules and RNA were examined using the HINT (Hydropathic INTeractions) computational model to obtain interaction scores that have been shown previously to be related to free energy. The calculations correlated well with experimental binding data, and the interaction scores were used to analyze the specific structural features of each aminoglycoside that contribute to the overall binding with the 16S rRNA. Our calculations indicate that, while ring I binds to the main binding pocket of the rRNA A-site, ring IV of paromomycin-based aminoglycosides contributes significantly to the overall binding.
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology & Drug Discovery, School of Pharmacy, Virginia Commonwealth University, Richmond 23298-0540, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Cashman
authors.forename: J P
authors.initials: JP
authors.lastname: Rife
authors.forename: G E
authors.initials: GE
authors.lastname: Kellogg
mesh_terms: D000465:Algorithms; D000617:Aminoglycosides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D004926:Escherichia coli / Q000235:genetics; D005839:Gentamicins / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010303:Paromomycin / Q000737:chemistry; D012336:RNA, Ribosomal, 16S / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D005839:Gentamicins; D012336:RNA, Ribosomal, 16S; D010303:Paromomycin