title: Molecular modeling studies on G-quadruplex complexes of telomerase inhibitors: structure-activity relationships.
abstract: Inhibition of the ability of the enzyme telomerase to add telomeric repeats to the end of chromosomes is a novel target for potential anticancer therapy. This paper examines the hypothesis that compounds possessing a planar aromatic chromophore inhibit telomerase via stabilization of, and binding to, a folded guanine quadruplex structure. Two series of telomerase inhibitors have been designed based on the 2,6-disubstituted amidoanthracene-9,10-dione and 3,6-disubstituted acridine chromophores in order to investigate structure-activity relationships between biological activity and substituent group size. The relative binding energies between these compounds and the folded human telomere DNA quadruplex were determined using molecular simulation methods, involving explicitly solvated structures. The results obtained are in excellent agreement with the biological activity as measured in vitro using a modified TRAP assay and in general agreement with the ranking order of binding enthalpies found in isothermal titration calorimetry studies. This broad agreement provides strong support for the hypothesis that guanine quadruplexes are the primary target for telomerase inhibitors with extended planar chromophores.
authors.affiliation: CRC Biomolecular Structure Unit, Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London SW3 6JB, U.K.
authors.forename: M A
authors.initials: MA
authors.lastname: Read
authors.forename: A A
authors.initials: AA
authors.lastname: Wood
authors.forename: J R
authors.initials: JR
authors.lastname: Harrison
authors.forename: S M
authors.initials: SM
authors.lastname: Gowan
authors.forename: L R
authors.initials: LR
authors.lastname: Kelland
authors.forename: H S
authors.initials: HS
authors.lastname: Dosanjh
authors.forename: S
authors.initials: S
authors.lastname: Neidle
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry*; D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002151:Calorimetry; D004247:DNA / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000737:chemistry
chemical_list: D000166:Acridines; D000880:Anthraquinones; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004247:DNA; D019098:Telomerase