Investigation of DNA-binding properties of an aminoglycoside-polyamine library using Quantitative Structure-Activity Relationship (QSAR) models

Kaushal Rege, Asif Ladiwala, Shanghui Hu, M. Breneman, Jonathan S. Dordick, Steven M. Cramer

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1854-1863
Number of pages10
JournalJournal of Chemical Information and Modeling
Volume45
Issue number6
DOIs
Publication statusPublished - Nov 2005
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Chemistry(all)
  • Computational Theory and Mathematics
  • Computer Science Applications
  • Information Systems

Cite this