TY - JOUR
T1 - Investigation of DNA-binding properties of an aminoglycoside-polyamine library using Quantitative Structure-Activity Relationship (QSAR) models
AU - Rege, Kaushal
AU - Ladiwala, Asif
AU - Hu, Shanghui
AU - Breneman, M.
AU - Dordick, Jonathan S.
AU - Cramer, Steven M.
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=28944444772&partnerID=8YFLogxK
U2 - 10.1021/ci050082g
DO - 10.1021/ci050082g
M3 - Article
C2 - 16309293
AN - SCOPUS:28944444772
SN - 1549-9596
VL - 45
SP - 1854
EP - 1863
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 6
ER -