DNA Complexing Minor Groove-Binding Ligands: Perspectives in Antitumour and Antimicrobial Drug Design

Abstract

DNA is the molecular target of many antimicrobial, antiviral and antitumour active drugs. In recent years DNA minor groove-binding ligands, possessing pronounced sequence specificity to the oligonucleotide matrix and derived from natural sources or by synthetic methods, have been studied frequently because of their sequence recognizing ability and, on the molecular level, for the elucidation of binding modes and specific structural interaction parameters. Fundamental questions arose both for medicinal chemist and molecular biologist: what is the DNA-sequence selective principle of DNA interacting drugs?, what are the consequences for a rational drug design?, and what are the molecular principles of the protein DNA sequence recognition process controlling gene expression? In this context this review discuses the chemistry and, in detail, the three dimensional structural aspects of the binding characteristics of low Mr minor groove-binding ligands towards the B-ONA. X-ray crystallographic techniques, high resolution NMR spectroscopic observations, DNase I footprinting studies and state-of-the-art computer molecular modelling are all valuable tools to unravel most of the unsolved problems. In this context the detailed experimental studies support effectively a rational drug design for the development of "DNA sequence-reading" drugs and will also help to understand gene expression at the molecular level.