title: Structure-based virtual screening for novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase and their experimental evaluation.
abstract: A public compound library with 260,000 compounds was screened virtually by computational docking for novel inhibitors of the transmembrane enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA). Docking was performed with the program GOLD in conjunction with a high resolution X-ray crystal structure of SERCA. Compounds that were predicted to be active were tested in bioassays. Nineteen novel compounds were discovered that were capable of inhibiting the ATP hydrolysis activity of SERCA at concentrations below 50 microM. Crucial enzyme/inhibitor interactions were identified by analyzing the docking-predicted binding poses of active compounds. Like other SERCA inhibitors, the newly discovered compounds are of considerable medicinal interest because of their potential for cancer chemotherapy.
authors.affiliation: Department of Chemistry, Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Deye
authors.forename: Christopher
authors.initials: C
authors.lastname: Elam
authors.forename: Michael
authors.initials: M
authors.lastname: Lape
authors.forename: Robert
authors.initials: R
authors.lastname: Ratliff
authors.forename: Kayla
authors.initials: K
authors.lastname: Evans
authors.forename: Stefan
authors.initials: S
authors.lastname: Paula
mesh_terms: D019295:Computational Biology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006873:Hydroquinones / Q000737:chemistry; D011487:Protein Conformation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006873:Hydroquinones; D054852:Small Molecule Libraries; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C031927:hydroquinone