Minor Groove Binders and Drugs Targeting Proteins Cover Complementary Regions in Chemical Shape Space

• Published in: Journal of chemical information and modeling Vol. 51; no. 9; pp. 2223 - 2232
• Main Authors: Fuchs, Julian E, Spitzer, Gudrun M, Javed, Ameera, Biela, Adam, Kreutz, Christoph, Wellenzohn, Bernd, Liedl, Klaus R
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 26.09.2011
• Subjects: Antineoplastic agents; Binding sites; Biochemistry; Biological and medical sciences; Calorimetry; Chemical Information; Chemistry; Chemotherapy; Databases, Protein; Deoxyribonucleic acid; DNA; DNA - chemistry; Exact sciences and technology; FDA approval; Fundamental and applied biological sciences. Psychology; Gene expression; General and physical chemistry; General. Nomenclature, chemical documentation, computer chemistry; Interactions. Associations; Intermolecular phenomena; Ligands; Medical sciences; Molecular and cellular biology; Molecular biophysics; Molecular genetics; Molecular Structure; Pharmaceutical Preparations - chemistry; Pharmacology. Drug treatments; Proteins; Proteins - chemistry; Spectrophotometry, Ultraviolet; Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry; Drug; Ligand binding; Ligand; Virtual screening; Molecular interaction; Medical screening; Experimental study; Gene expression; Protein; Relevance; Computational chemistry; DNA; Biopolymer; Genetic engineering; Bioinformatics
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci200237c

DNA minor groove binders (MGBs) are known to influence gene expression and are therefore widely studied to explore their therapeutic potential. We identified shape-based virtual screening with ROCS as a highly effective computational approach to enrich known MGBs in top-ranked molecules. Discovery of ten previously unknown MGBs by shape-based screening further confirmed the relevance of ligand shape for minor groove affinity. Based on experimental testing we propose three simple rules (at least two positive charges, four nitrogen atoms, and one aromatic ring) as filters to reach even better enrichment of true positives in ROCS hit lists. Interestingly, shape-based ranking of MGBs versus FDA-approved drugs again leads to high enrichment rates, indicating complementary coverage of chemical shape space and indicating minor groove affinity to be unfavorable for approval of drugs targeting proteins.