title: Finding potential DNA-binding compounds by using molecular shape.
abstract: For the first time a general shape-search docking algorithm (DOCK) has been applied to the minor and major grooves of A-, B- and Z-type DNA dodecamers and to an intercalation site in a B-DNA-type hexamer. Both experimentally and theoretically derived geometries for the various DNA fragments were used. The DOCK searches were carried out on a subset of the Cambridge Crystallographic Database, consisting of almost 10,000 molecules. One of the molecules that scored best in terms of the DOCK algorithm was CC-1065, a potent antitumor agent known to (covalently) bind the AT-rich parts of the minor groove of B-DNA. Several known DNA-binding agents also scored highly. Molecules with shapes complementary to A-, B- and Z-type DNA were indicated by DOCK. In addition, compounds were extracted from the database that might be selective for the GC-rich regions of the minor groove of B-DNA. Many of the compounds in the present study may serve as a starting point for further molecular design of novel DNA-binding ligands.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Grootenhuis
authors.forename: D C
authors.initials: DC
authors.lastname: Roe
authors.forename: P A
authors.initials: PA
authors.lastname: Kollman
authors.forename: I D
authors.initials: ID
authors.lastname: Kuntz
mesh_terms: D000465:Algorithms; D001482:Base Composition; D001483:Base Sequence; D001665:Binding Sites; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D066298:In Vitro Techniques; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D007364:Intercalating Agents; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D004247:DNA