Molecular determinants of topoisomerase I poisoning by lamellarins: comparison with camptothecin and structure-activity relationships.

Abstract	A series of lamellarin derivatives have been studied as topoisomerase I (Top1) inhibitors. Molecular models of the ternary complexes formed between the DNA-Top1 ensemble and lamellarin D (LMD) or camptothecin (CPT) fully intercalated into the duplex DNA have been built and studied by means of nanosecond molecular dynamics simulations in aqueous solution. Our results show that the 20-OH and 8-OH of LMD can participate in hydrogen-bonding interactions with the side chains of Glu356 and Asn722, respectively, the latter being consistent with the finding that CEM/C2 cells, which are resistant to CPT, are cross-resistant to LMD. Our models also account for the observation that LMD stabilizes Top1 cleavage at CG sites in addition to the TG sites observed for CPT and rationalize the structure-activity relationships within the series. The deleterious effect of replacing the 20-OH in LMD with a hydrogen was confirmed using a set of thermodynamic integration free energy simulations.
Authors	Esther Marco, William Laine, Christelle Tardy, Amélie Lansiaux, Masatomo Iwao, Fumito Ishibashi, Christian Bailly, Federico Gago
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 11 Pg. 3796-807 (Jun 02 2005) ISSN: 0022-2623 [Print] United States
PMID	15916431 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Coumarins Heterocyclic Compounds, 4 or More Rings Intercalating Agents Isoquinolines Topoisomerase I Inhibitors lamellarin D DNA Topoisomerases, Type I Camptothecin
Topics	Antineoplastic Agents (chemistry, pharmacology) Camptothecin (chemistry, pharmacology) Cell Line, Tumor Computer Simulation Coumarins (chemistry, pharmacology) DNA Topoisomerases, Type I (chemistry) Drug Resistance, Neoplasm Heterocyclic Compounds, 4 or More Rings (chemistry, pharmacology) Humans Intercalating Agents (chemistry, pharmacology) Isoquinolines (chemistry, pharmacology) Models, Molecular Protein Binding Structure-Activity Relationship Thermodynamics Topoisomerase I Inhibitors

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!