title: Virtual screening and biophysical studies lead to HSP90 inhibitors.
abstract: Heat shock protein 90 (HSP90) is a molecular chaperone that plays important functional roles in cells. The chaperone activity of HSP90 is regulated by the hydrolysis of ATP at the protein's N-terminal domain. HSP90, in particular the N-terminal domain, is a current inhibition target for therapeutic treatments of cancers. This paper describes an application of virtual screening, thermal shift assaying and protein NMR spectroscopy leading to the discovery of HSP90 inhibitors that contain the resorcinol structure. The resorcinol scaffold can be found in a class of HSP90 inhibitors that are currently undergoing clinical trials. The proved success of the resorcinol moiety in HSP90 inhibitors validates this combined virtual screen and biophysical technique approach, which may be applied for future inhibitor discovery work for HSP90 as well as other targets.
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand.
authors.forename: Renjie
authors.initials: R
authors.lastname: Huang
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Ayine-Tora
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand.
authors.forename: M Nasri
authors.initials: MN
authors.lastname: Muhammad Rosdi
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand. Electronic address: j.reynisson@auckland.ac.nz.
authors.forename: Jóhannes
authors.initials: J
authors.lastname: Reynisson
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand. Electronic address: i.leung@auckland.ac.nz.
authors.forename: Ivanhoe K H
authors.initials: IKH
authors.lastname: Leung
mesh_terms: D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D057166:High-Throughput Screening Assays; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D018841:HSP90 Heat-Shock Proteins
keywords: HSP90; Inhibitor; Protein NMR; Thermal shift assay; Virtual screening