Rege Kaushal, Ladiwala Asif, Hu Shanghui, Breneman Curt M, Dordick Jonathan S, Cramer Steven M
Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA.
J Chem Inf Model. 2005 Nov-Dec;45(6):1854-63. doi: 10.1021/ci050082g.
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.
