DNA Minor Groove Pharmacophores Describing Sequence Specific Properties

• Published in: Journal of chemical information and modeling 2007-07, Vol.47 (4), p.1580-1589
• Main Authors: Spitzer, Gudrun M, Wellenzohn, Bernd, Laggner, Christian, Langer, Thierry, Liedl, Klaus R
• Format: Article
• Language: English
• Subjects: Base Sequence; Binding sites; Chemistry, Pharmaceutical; Deoxyribonucleic acid; Distamycins - chemistry; DNA; DNA - chemistry; Gene expression; Genomics; Hydrogen Bonding; Ligands; Models, Molecular; Molecular Sequence Data; Molecular Structure; Molecules; Pharmacology; Proteins
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci600500v

The more that is known about human and other genome sequences and the correlation between gene expression and the course of a disease, the more evident it seems to be that DNA is chosen as a drug target instead of proteins which are built with the information encoded by DNA. According to this approach, small minor groove binding molecules have been designed to bind the DNA sequence specifically and thereby downregulate genes. Because of their lack of druglikeness, we plan to use them as templates for forthcoming virtual screening experiments to discover molecules with the same bioactivity and a different scaffold. In this proof of principle study, carried out with the software tool Catalyst, we present a model work for description of a ligand−DNA complex with the aid of pharmacophore modeling methods. The successful reproduction of sequence specificity of a polyamidic minor groove binding ligand is the precondition for later model application to virtual screening.