title: Novel phenolic inhibitors of the sarco/endoplasmic reticulum calcium ATPase: identification and characterization by quantitative structure-activity relationship modeling and virtual screening.
abstract: Inhibitors of the sarco/endoplasmic reticulum calcium ATPase (SERCA) are valuable research tools and hold promise as a new generation of anti-prostate cancer agents. Based on previously determined potencies of phenolic SERCA inhibitors, we created quantitative structure-activity relationship (QSAR) models using three independent development strategies. The obtained QSAR models facilitated virtual screens of several commercial compound collections for novel inhibitors. Sixteen compounds were subsequently evaluated in SERCA activity inhibition assays and 11 showed detectable potencies in the micro- to millimolar range. The experimental results were then incorporated into a comprehensive master QSAR model, whose physical interpretation by partial least squares analysis revealed that properly positioned substituents at the central phenyl ring capable of forming hydrogen bonds and of undergoing hydrophobic interactions were prerequisites for effective SERCA inhibition. The established SAR was in good agreement with findings from previous structural studies, even though it was obtained independently using standard QSAR methodologies.
authors: Department of Chemistry, Northern Kentucky University , Highland Heights, KY , USA .
authors: Stefan
authors: S
authors: Paula
authors: Emily
authors: E
authors: Hofmann
authors: John
authors: J
authors: Burden
authors: David T
authors: DT
authors: Stanton
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D062126:Databases, Chemical; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D016018:Least-Squares Analysis; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014584:User-Computer Interface
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010636:Phenols; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506943:ATP2A1 protein, human
keywords: Calcium homeostasis; P-type ATPase; calcium ion transport; in silico screening; inhibitory potency; partial least squares analysis