Further insight into the DNA recognition mechanism of trabectedin from the differential affinity of its demethylated analogue ecteinascidin ET729 for the triplet DNA binding site CGA.
Trabectedin and its N12-demethylated analogue ET729 bind covalently to the central guanine of selected DNA triplets. Although both drugs equally target several sites, including AGA, we show that covalent modification of CGA is only achieved by ET729. By means of molecular dynamics simulations of the precovalent complexes, we explain in atomic detail how such a simple structural modification brings about this notable change in the DNA-binding selectivity profiles of these two drugs.
Marco
Esther
E
Departamento de Farmacología, Universidad de Alcalá, Madrid, Spain.
David-Cordonnier
Marie-Hélène
MH
Bailly
Christian
C
Cuevas
Carmen
C
Gago
Federico
F
D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry*; D001665:Binding Sites; D004247:DNA / Q000737:chemistry*; D004149:Dioxoles / Q000737:chemistry*; D007546:Isoquinolines / Q000737:chemistry*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry*; D000077606:Trabectedin
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C100350:ecteinascidin 729; D004247:DNA; D000077606:Trabectedin