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.

In silico approaches for drug repurposing in oncology: a scoping review

“…Regarding study design, we sought to investigate if the publications fit into a broad categorization of the in silico strategies. We found that most studies solely used computational methods without further testing their findings in other scientific settings (46.64%) (Shah et al, 2012;Abazeed et al, 2013;Ain et al, 2013;Eichhorn et al, 2013;Emig et al, 2013;Leung et al, 2013;Liu et al, 2013Liu et al, , 2020Liu et al, , 2021Menden et al, 2013;Naresh et al, 2013;Omotuyi et al, 2013;Singh et al, 2013;Chen, 2014;Dean et al, 2014;Xu and Wang, 2014;Chuang et al, 2015;Dunna et al, 2015;Gustafson et al, 2015;Hammad and Azam, 2015;Kaur et al, 2015;Paula et al, 2015;Rubio-Perez et al, 2015;Sarvagalla et al, 2015;Zhang et al, 2015;Brown et al, 2016;Gayvert et al, 2016;Lee et al, 2016;Shafique et al, 2016;Tan, 2016;Verma et al, 2016;Spiliotopoulos et al, 2017aSpiliotopoulos et al, , 2017bJadhav and Karuppayil, 2017;Kabir et al, 2017Kabir et al, , 2018Kabir et al, , 2019Khanam et al, 2017;Salentin et al, 2017;…”

Sarco/Endoplasmic Reticulum Calcium ATPase Inhibitors: Beyond Anticancer Perspective

“…Nevertheless, in the meantime, novel SERCA-inhibiting hydroquinone and phenolic compounds were identified based on quantitative structure−activity relationship (QSAR) modeling. 166 Although the specificity of compound 2 as SERCA inhibitor is not absolute, recently, SERCA inhibitors 1 and 2 were also found to significantly increase the lifespan of Caenorhabditis elegans. 167 Particularly compound 2 as a reversible SERCA inhibitor, but also compound 1 as irreversible one, changed the lifespan in a bell-shaped concentration manner of both wild type and caloric restriction eat-2 mutant of C. elegans, highlighting the multipotentiality of calcium signaling modulation and the importance of its research.…”

“…Therefore, the effect of compound 2 studied in rat ventricular myocytes is not surely SERCA-specific. − It remains to be elucidated if derivatization of the compound 2 structure could resolve this issue. Nevertheless, in the meantime, novel SERCA-inhibiting hydroquinone and phenolic compounds were identified based on quantitative structure–activity relationship (QSAR) modeling …”

DataSheet2.PDF

“…Regarding study design, we sought to investigate if the publications fit into a broad categorization of the in silico strategies. We found that most studies solely used computational methods without further testing their findings in other scientific settings (46.64%) (Shah et al, 2012;Abazeed et al, 2013;Ain et al, 2013;Eichhorn et al, 2013;Emig et al, 2013;Leung et al, 2013;Liu et al, 2013Liu et al, , 2020Liu et al, , 2021Menden et al, 2013;Naresh et al, 2013;Omotuyi et al, 2013;Singh et al, 2013;Chen, 2014;Dean et al, 2014;Xu and Wang, 2014;Chuang et al, 2015;Dunna et al, 2015;Gustafson et al, 2015;Hammad and Azam, 2015;Kaur et al, 2015;Paula et al, 2015;Rubio-Perez et al, 2015;Sarvagalla et al, 2015;Zhang et al, 2015;Brown et al, 2016;Gayvert et al, 2016;Lee et al, 2016;Shafique et al, 2016;Tan, 2016;Verma et al, 2016;Spiliotopoulos et al, 2017aSpiliotopoulos et al, , 2017bJadhav and Karuppayil, 2017;Kabir et al, 2017Kabir et al, , 2018Kabir et al, , 2019Khanam et al, 2017;Salentin et al, 2017;…”