title: Minor groove binders and drugs targeting proteins cover complementary regions in chemical shape space.
abstract: 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.
authors.affiliation: Faculty of Chemistry and Pharmacy, University of Innsbruck, Innsbruck, Austria.
authors.forename: Julian E
authors.initials: JE
authors.lastname: Fuchs
authors.forename: Gudrun M
authors.initials: GM
authors.lastname: Spitzer
authors.forename: Ameera
authors.initials: A
authors.lastname: Javed
authors.forename: Adam
authors.initials: A
authors.lastname: Biela
authors.forename: Christoph
authors.initials: C
authors.lastname: Kreutz
authors.forename: Bernd
authors.initials: B
authors.lastname: Wellenzohn
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
mesh_terms: D002151:Calorimetry; D004247:DNA / Q000737:chemistry*; D030562:Databases, Protein; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D004364:Pharmaceutical Preparations; D011506:Proteins; D004247:DNA