Investigation of DNA-binding properties of an aminoglycoside-polyamine library using quantitative structure-activity relationship (QSAR) models

J Chem Inf Model. Nov-Dec 2005;45(6):1854-63. doi: 10.1021/ci050082g.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminoglycosides / chemistry
  • Aminoglycosides / metabolism*
  • Carbohydrate Sequence
  • DNA / chemistry
  • DNA / metabolism*
  • Deoxyadenosines / chemistry
  • Drug Evaluation, Preclinical
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Polyamines / chemistry
  • Polyamines / metabolism*
  • Quantitative Structure-Activity Relationship

Substances

  • Aminoglycosides
  • Deoxyadenosines
  • Ligands
  • Polyamines
  • DNA
  • 2'-deoxyadenosine