Minor Groove of DNA as Target for Drug Design

Small minor groove binding molecules have been found to influence DNA-dependent processes. Their affinity is high enough to prevent transcription factors from interaction with the DNA. Some of the minor groove binders can be even designed to target only specific DNA sequences. Thereby, they are able to influence transcription, which provides the possibility to systematically regulate the synthesis of proteins. Unfortunately, all highly sequence-selective minor groove binders have the same structural scaffold, which includes a number of amide bonds, and therefore lack metabolic stability. We adopted methods originating from chemoinformatics to merge experimental data with our knowledge on the dynamics of the biomolecular interface of DNA. We demonstrated that we are able to reproduce sequence specificity by a pharmacophore modeling approach [1] and built a comprehensive database containing all known minor groove interactions within complexes of DNA with different ligands [2]. An analysis of the database revealed that the known minor groove binding scaffolds are far from optimally fitting the hydrogen bonding patterns presented by DNA [3]. Therefore, screened compound databases for new ligands. We validated the ligands by isothermal titration calorimetry to understand the thermodynamics of ligand binding [4].