Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

SummaryUsing 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.

[1]  R. L. Jones,et al.  The effect of ionic strength on DNA-ligand unwinding angles for acridine and quinoline derivatives. , 1980, Nucleic acids research.

[2]  P. Jones,et al.  Kefir consumption does not alter plasma lipid levels or cholesterol fractional synthesis rates relative to milk in hyperlipidemic men: a randomized controlled trial [ISRCTN10820810] , 2002, BMC complementary and alternative medicine.

[3]  J N Weinstein,et al.  Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin. , 1998, Journal of medicinal chemistry.

[4]  T. Yamori,et al.  In vitro cytotoxicity of the protoberberine-type alkaloids. , 2001, Journal of natural products.

[5]  A. R. Srinivasan,et al.  Minor groove-directed and intercalative ligand-DNA interactions in the poisoning of human DNA topoisomerase I by protoberberine analogs. , 1997, Biochemistry.

[6]  P. Pantazis,et al.  The camptothecins : from discovery to the patient , 1996 .

[7]  P. Canal,et al.  Toxicity Patterns of Cytotoxic Drugs , 2003, Investigational New Drugs.

[8]  H. Strutt,et al.  Camptothecin cytotoxicity in mammalian cells is associated with the induction of persistent double strand breaks in replicating DNA. , 1991, Nucleic acids research.

[9]  Y. Pommier,et al.  Human topoisomerase I inhibition: docking camptothecin and derivatives into a structure-based active site model. , 2002, Biochemistry.

[10]  F. Arvelo,et al.  Structural modification of berberine alkaloids in relation to cytotoxic activity in vitro. , 2000, Journal of ethnopharmacology.

[11]  A. Clark,et al.  Antimicrobial properties of alkaloids from Xanthorhiza simplicissima. , 1994, Journal of pharmaceutical sciences.

[12]  J. Champoux,et al.  Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. , 1998, Science.

[13]  B. Yung,et al.  Berberine complexes with DNA in the berberine-induced apoptosis in human leukemic HL-60 cells. , 1995, Cancer letters.

[14]  Lance Stewart,et al.  The mechanism of topoisomerase I poisoning by a camptothecin analog , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[15]  W. Wilson,et al.  The interaction of plant alkaloids with DNA. II. Berberinium chloride. , 1977, Nucleic acids research.

[16]  Y. Pommier,et al.  Position-specific trapping of topoisomerase I-DNA cleavage complexes by intercalated benzo[a]- pyrene diol epoxide adducts at the 6-amino group of adenine. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  A. R. Srinivasan,et al.  Human topoisomerase I poisoning by protoberberines: potential roles for both drug-DNA and drug-enzyme interactions. , 2000, Biochemistry.

[18]  T. Mizukami,et al.  Inhibitors of DNA topoisomerase I and II isolated from the Coptis rhizomes. , 1995, Planta medica.

[19]  R. Hertzberg,et al.  Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. , 1985, The Journal of biological chemistry.

[20]  W. Denny,et al.  Crystal structure of 9-amino-N-[2-(4-morpholinyl)ethyl]-4-acridinecarboxamide bound to d(CGTACG)2: implications for structure-activity relationships of acridinecarboxamide topoisomerase poisons. , 2002, Nucleic acids research.

[21]  G. Kuttan,et al.  Role of Berberine as an Adjuvant Response Modifier During Tumour Therapy in Mice , 1999 .

[22]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[23]  L. Cipak,et al.  Effect of berberine on proliferation, cell cycle and apoptosis in HeLa and L1210 cells , 2003, The Journal of pharmacy and pharmacology.

[24]  S. Moro,et al.  Sequence-specific interactions of drugs interfering with the topoisomerase-DNA cleavage complex. , 2002, Biochimica et biophysica acta.

[25]  G. Chillemi,et al.  Structure and hydration of the DNA-human topoisomerase I covalent complex. , 2001, Biophysical journal.

[26]  D. S. Pilch,et al.  A structural model for the ternary cleavable complex formed between human topoisomerase I, DNA, and camptothecin. , 2001, Biochemistry.

[27]  Nicholas R. Cozzarelli,et al.  DNA topology and its biological effects , 1990 .

[28]  Olga Kennard,et al.  Systematic analysis of structural data as a research technique in organic chemistry , 1983 .

[29]  R. Snapka,et al.  SV40 DNA replication intermediates: Analysis of drugs which target mammalian DNA replication , 1993, BioEssays : news and reviews in molecular, cellular and developmental biology.

[30]  K. Bastow,et al.  The 9-position in berberine analogs is an important determinant of DNA topoisomerase II inhibition. , 2000, Anti-cancer drug design.

[31]  Luhua Lai,et al.  Further development and validation of empirical scoring functions for structure-based binding affinity prediction , 2002, J. Comput. Aided Mol. Des..