title: Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model.
abstract: Using the X-ray crystal structure of the human topoisomerase I (top1) - DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad range of the top1-poisoning activities. This model has the drug intercalated with its planar chromophore between the -1 and +1 base pairs flanking the cleavage site, with the nonplanar portion pointing into the minor groove. The ternary complexes were geometry-optimized and relative interaction energies, computed by using the Tripos force field, were found to rank in correct order the biological potency of the compounds; in addition, the model is also consistent with the top1-poisoning inactivity of berberine, a major prototype of the protoberberine alkaloids. The model might serve as a rational basis for elaboration of the most active compound as a lead structure, in order to develop more potent top1 poisons as next generation anti-cancer drugs.
authors.affiliation: Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia. kettmann@fpharm.uniba.sk
authors.forename: Viktor
authors.initials: V
authors.lastname: Kettmann
authors.forename: Daniela
authors.initials: D
authors.lastname: Kost'álová
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Höltje
mesh_terms: D001600:Berberine Alkaloids / Q000506:poisoning*; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D046911:Macromolecular Substances; D008958:Models, Molecular; D008968:Molecular Conformation; D013816:Thermodynamics
chemical_list: D001600:Berberine Alkaloids; D008024:Ligands; D046911:Macromolecular Substances; C009090:protoberberine; D004264:DNA Topoisomerases, Type I