title: 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.affiliation: Departamento de Farmacología, Universidad de Alcalá, E-28871 Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Marco
authors.forename: William
authors.initials: W
authors.lastname: Laine
authors.forename: Christelle
authors.initials: C
authors.lastname: Tardy
authors.forename: Amélie
authors.initials: A
authors.lastname: Lansiaux
authors.forename: Masatomo
authors.initials: M
authors.lastname: Iwao
authors.forename: Fumito
authors.initials: F
authors.lastname: Ishibashi
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002166:Camptothecin / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D006576:Heterocyclic Compounds, 4 or More Rings; D007364:Intercalating Agents; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; C455554:lamellarin D; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin