title: Dimeric and trimeric triazole based molecules as a new class of Hsp90 molecular chaperone inhibitors.
abstract: In the last decade Hsp90 inhibitors have emerged as attractive candidates for the development of new potent anticancer therapeutics. In order to identify novel agents able to block the chaperone activity, following a structure-based approach, we used in silico screening to direct the synthesis of potential inhibitors bearing the triazole scaffold, a widespread motif in drug-like molecules. Docking results, performed on a larger collection of dimeric and trimeric triazole derivatives, suggested the synthesis of some molecules showing different calculated binding energies and modes. Surface Plasmon Resonance Binding assay, performed on the synthesized compounds, allow to identify a series of molecules able to potently interact with the target enzyme and to disclose an interesting hit: compound 2b showed to interact with the ATP binding site in the N-terminus domain of Hsp90 and to efficiently inhibit the chaperone activity.
authors.affiliation: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, SA, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Terracciano
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Chini
authors.forename: Fabrizio Dal
authors.initials: FD
authors.lastname: Piaz
authors.forename: Antonio
authors.initials: A
authors.lastname: Vassallo
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
authors.forename: Ines
authors.initials: I
authors.lastname: Bruno
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
mesh_terms: D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D014230:Triazoles
keywords: Docking; Hsp90 inhibitors; Molecular chaperone; Triazole derivatives