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.

• Calcium homeostasis
• calcium ion transport
• inhibitory potency
• in silico screening
• P-type ATPase
• partial least squares analysis

Declaration of interest

The authors report no declaration of interest.

This work was supported by grants from the Kentucky Biomedical Research Infrastructure Network (P20GM103436-12) and the National Institutes of Health (1R15GM084431-01 and 2R15GM084431-02) to S.P. Moreover, J.B. is grateful to the School of Natural Science at Spalding University for the purchase of some of the test compounds and for covering software license fees.

Supplementary material available online

Supplementary Tables S1–S3 Supplementary Figures S1 and S2