title: Investigation of DNA-binding properties of an aminoglycoside-polyamine library using quantitative structure-activity relationship (QSAR) models.
abstract: We have recently developed a novel multivalent cationic library based on the derivatization of aminoglycosides by linear polyamines. In the current study, we describe the DNA-binding activity of this library. Screening results indicated that several candidates from the library showed high DNA-binding activities with some approaching those of cationic polymers. Quantitative Structure-Activity Relationship (QSAR) models of the screening data were employed to investigate the physicochemical effects governing polyamine-DNA binding. The utility of these models for the a priori prediction of polyamine-DNA-binding affinity was also demonstrated. Molecular descriptors selected in the QSAR modeling indicated that molecular size, basicity, methylene group spacing between amine centers, and hydrogen-bond donor groups of the polyamine ligands were important contributors to their DNA-binding efficacy. The research described in this paper has led to the development of new multivalent ligands with high DNA-binding activity and improved our understanding of structure-activity relationships involved in polyamine-DNA binding. These results have implications for the discovery of novel polyamine ligands for nonviral gene delivery, plasmid DNA purification, and anticancer therapeutics.
authors.affiliation: Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA.
authors.forename: Kaushal
authors.initials: K
authors.lastname: Rege
authors.forename: Asif
authors.initials: A
authors.lastname: Ladiwala
authors.forename: Shanghui
authors.initials: S
authors.lastname: Hu
authors.forename: Curt M
authors.initials: CM
authors.lastname: Breneman
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Dordick
authors.forename: Steven M
authors.initials: SM
authors.lastname: Cramer
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry / Q000378:metabolism*; D002240:Carbohydrate Sequence; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D003839:Deoxyadenosines / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D003839:Deoxyadenosines; D008024:Ligands; D011073:Polyamines; D004247:DNA; C058118:2'-deoxyadenosine