title: The polymorphisms of DNA G-quadruplex investigated by docking experiments with telomestatin enantiomers.
abstract: Human telomeres are comprised of d(TTAGGG) repeats involved in the formation of G-quadruplex DNA structures. Ligands stabilizing these G-quadruplex DNA structures are potential inhibitors of the cancer cell-associated enzyme telomerase. In human cells, telomerase adds multiple copies of the 5'-GGTTAG-3' motif to the end of the G-strand of the telomere and in the majority of tumor cells it results over-expressed. Several structural studies have revealed a diversity of topologies for telomeric quadruplexes, which are sensitive to the nature of the cations present, to the flanking sequences, and probably also to concentration, as confirmed by the different conformations deposited in the Protein Data Bank (PDB). The existence of different polymorphisms in the DNA quadruplex and the absence of a uniquely precise binding site prompted us to carefully compare the two different docking approaches: MOLINE and Auto- Dock. As target we have selected six different experimental models of the human telomeric sequence d[AG3(T2AG3)3] based on three Gtetrads and as ligands the telomestatin isomers, whose the S enantomer is experimentally known to recognize the G-quadruplex better than the R one. In this communication we discuss the different binding modes of the well known strong telomestatin G-quadruplex binder form the thermodynamic and the geometrical points of view. With respect to this last issue we propose an easy approach to classify binding modes of G-quadruplex ligands based on a single angle descriptor as tool for the quick analysis of the binding modes.
authors.affiliation: Dipartimento di Scienze della Salute, Universita Magna Gracia di Catanzaro, Catanzaro, Italy. alcaro@unicz.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Giosue
authors.initials: G
authors.lastname: Costa
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.forename: Federica
authors.initials: F
authors.lastname: Moraca
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.forename: Lucia
authors.initials: L
authors.lastname: Parrotta
authors.forename: Anna
authors.initials: A
authors.lastname: Artese
mesh_terms: D001665:Binding Sites; D004247:DNA / Q000737:chemistry*; D054856:G-Quadruplexes; D006801:Humans; D008958:Models, Molecular; D010080:Oxazoles / Q000737:chemistry*; D013237:Stereoisomerism; D016615:Telomere
chemical_list: D010080:Oxazoles; C431888:telomestatin; D004247:DNA