Discovery of novel SERCA inhibitors by virtual screening of a large compound library

Two screening protocols based on recursive partitioning and computational ligand docking methodologies, respectively, were employed for virtual screens of a compound library with 345,000 entries for novel inhibitors of the enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA), a potential target for cancer chemotherapy. A total of 72 compounds that were predicted to be potential inhibitors of SERCA were tested in bioassays and 17 displayed inhibitory potencies at concentrations below 100 μM. The majority of these inhibitors were composed of two phenyl rings tethered to each other by a short link of one to three atoms. Putative interactions between SERCA and the inhibitors were identified by inspection of docking-predicted poses and some of the structural features required for effective SERCA inhibition were determined by analysis of the classification pattern employed by the recursive partitioning models.

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► 17 novel SERCA inhibitors are presented that were discovered by virtual screening of a compound library.
► Recursive partitioning methodology was successfully applied for the identification of SERCA inhibitors via virtual screening.
► Most SERCA inhibitors described in this study are bisphenol derivatives or analogs of hydroquinone.