Structure-based virtual screening for novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase and their experimental evaluation.
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.
Deye
Joel
J
Department of Chemistry, Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, USA.
Elam
Christopher
C
Lape
Michael
M
Ratliff
Robert
R
Evans
Kayla
K
Paula
Stefan
S
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
D004791:Enzyme Inhibitors; D006873:Hydroquinones; D054852:Small Molecule Libraries; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C031927:hydroquinone