Structure-based virtual screening for novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase and their experimental evaluation

Deye, Joel R.; Elam, Christopher; Lape, Michael; Ratliff, Robert L.; Evans, Kayla; Paula, Stefan

doi:10.1016/j.bmc.2008.12.010

Cited by 14 publications

(31 citation statements)

References 55 publications

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“…The stabilization involves hydrogen bonds between the two hydroxyl groups of BHQ, one with Asp59 on transmembrane helix M1 and the other with Pro308 on transmembrane helix M4 [47]. The BHQ binding pocket appears to be quite tolerant since a large number of bulky structures containing up to three aromatic rings tethered to each other have been characterized as novel SERCA inhibitors by computational docking [48], [49]. Large inhibitors protrude from the binding pocket and many of them present a characteristic 90 o bend.…”

Section: Discussionmentioning

confidence: 99%

Inhibition Mechanism of the Intracellular Transporter Ca2+-Pump from Sarco-Endoplasmic Reticulum by the Antitumor Agent Dimethyl-Celecoxib

et al. 2014

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Dimethyl-celecoxib is a celecoxib analog that lacks the capacity as cyclo-oxygenase-2 inhibitor and therefore the life-threatening effects but retains the antineoplastic properties. The action mechanism at the molecular level is unclear. Our in vitro assays using a sarcoplasmic reticulum preparation from rabbit skeletal muscle demonstrate that dimethyl-celecoxib inhibits Ca2+-ATPase activity and ATP-dependent Ca2+ transport in a concentration-dependent manner. Celecoxib was a more potent inhibitor of Ca2+-ATPase activity than dimethyl-celecoxib, as deduced from the half-maximum effect but dimethyl-celecoxib exhibited higher inhibition potency when Ca2+ transport was evaluated. Since Ca2+ transport was more sensitive to inhibition than Ca2+-ATPase activity the drugs under study caused Ca2+/Pi uncoupling. Dimethyl-celecoxib provoked greater uncoupling and the effect was dependent on drug concentration but independent of Ca2+-pump functioning. Dimethyl-celecoxib prevented Ca2+ binding by stabilizing the inactive Ca2+-free conformation of the pump. The effect on the kinetics of phosphoenzyme accumulation and the dependence of the phosphoenzyme level on dimethyl-celecoxib concentration were independent of whether or not the Ca2+–pump was exposed to the drug in the presence of Ca2+ before phosphorylation. This provided evidence of non-preferential interaction with the Ca2+-free conformation. Likewise, the decreased phosphoenzyme level in the presence of dimethyl-celecoxib that was partially relieved by increasing Ca2+ was consistent with the mentioned effect on Ca2+ binding. The kinetics of phosphoenzyme decomposition under turnover conditions was not altered by dimethyl-celecoxib. The dual effect of the drug involves Ca2+-pump inhibition and membrane permeabilization activity. The reported data can explain the cytotoxic and anti-proliferative effects that have been attributed to the celecoxib analog. Ligand docking simulation predicts interaction of celecoxib and dimethyl-celecoxib with the intracellular Ca2+ transporter at the inhibition site of hydroquinones.

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Section: Discussionmentioning

confidence: 99%

Inhibition Mechanism of the Intracellular Transporter Ca2+-Pump from Sarco-Endoplasmic Reticulum by the Antitumor Agent Dimethyl-Celecoxib

et al. 2014

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“…To this end, the most potent compounds capable of inhibiting in the submicromolar concentration range are hydroquinones with two identical bulky alkyl residues in positions 2 and 5. In a recently conducted structure-based virtual screen, we identified several novel monosubstituted hydroquinones carrying aryl groups that displayed inhibitory potencies in the low micromolar range 27. This was a somewhat surprising finding since previous evidence had suggested that two substituents were an absolute requirement for inhibitory potency 20.…”

Section: Introductionmentioning

confidence: 87%

“…This was a somewhat surprising finding since previous evidence had suggested that two substituents were an absolute requirement for inhibitory potency 20. Even though the SAR obtained in the study above 27 provided valuable insights into SERCA/inhibitor interactions, it was limited by the availability of compounds.…”

Section: Introductionmentioning

confidence: 88%

“…In a few previous studies, we and others started investigating systematically the molecular determinants of SERCA inhibition by BHQ and its analogues 20, 27-29. To this end, the most potent compounds capable of inhibiting in the submicromolar concentration range are hydroquinones with two identical bulky alkyl residues in positions 2 and 5.…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of hydroquinone derivatives as novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase

Paula

Abell

Deye

et al. 2009

Bioorganic & Medicinal Chemistry

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Analogues of the compound 2,5-di-tert-butylhydroquinone (BHQ) are capable of inhibiting the enzyme sarco/endoplasmic reticulum ATPase (SERCA) in the low micromolar and submicromolar concentration ranges. Not only are SERCA inhibitors valuable research tools, but they also have potential medicinal value as agents against prostate cancer. This study describes the synthesis of thirteen compounds representing several classes of BHQ analogues, such as hydroquinones with a single aromatic substituent, symmetrically and unsymmetrically disubstituted hydroquinones, and hydroquinones with ω-amino acid tethers attached to their hydroxyl groups. Structure-activity relationships were established by measuring the inhibitory potencies of all synthesized compounds in bioassays. The assays were complemented by computational ligand docking for an analysis of the relevant ligand/receptor interactions.

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“…Inhibitory potencies of the four synthesized BHQ analogs were determined spectroscopically in a coupled assay using SERCA prepared as rabbit microsomes as described previously [14], [15]. Rates of SERCA-catalyzed ATP hydrolysis coupled to NADH oxidation via the action of pyruvate kinase and lactate dehydrogenase were measured at different inhibitor concentrations.…”

Section: B Measurement Of Inhibitory Potenciesmentioning

confidence: 99%

Hydroquinones with Conformationally Constrained Substituents: Synthesis, Characterization, and Evaluation as Calcium–ATPase Inhibitors

Paula¹,

Elam²,

Woeste³

et al. 2013

IJBBB

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Abstract-Derivatives of the compound 2,5-di-tert-butylhydroquinone (BHQ) are inhibitors of the sarco/endoplasmic reticulum calcium ATPase (SERCA). Previous work identified BHQ analogs with two alkyl substituents composed of four to six carbon atoms as the most potent representatives from this inhibitor class. In this study, we explored the effects of introducing two cycloalkyl substituents on the hydroquinone scaffold. Since these substituents have limited conformational flexibility, the entropy penalty upon binding of these compounds to SERCA was expected to be smaller than for non-cyclic BHQ analogs, potentially conveying higher inhibitory potency. We synthesized a congeneric series of four 2,5-disubstituted BHQ analogs and determined their inhibitory potencies against SERCA in bioassays. Potencies were found in the low micromolar and submicromolar concentration ranges, making the new compounds some of the most potent hydroquinone-based inhibitors to date. Computational docking facilitated a detailed analysis of enzyme/inhibitor interactions at the molecular level and showed that the entropic effect was noticeable but too small to increase potency in a substantial manner.Index Terms-Calcium homeostasis, enzyme inhibition, P-type ATPase, medicinal chemistry.

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Structure-based virtual screening for novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase and their experimental evaluation

Cited by 14 publications

References 55 publications

Inhibition Mechanism of the Intracellular Transporter Ca2+-Pump from Sarco-Endoplasmic Reticulum by the Antitumor Agent Dimethyl-Celecoxib

Inhibition Mechanism of the Intracellular Transporter Ca2+-Pump from Sarco-Endoplasmic Reticulum by the Antitumor Agent Dimethyl-Celecoxib

Design, synthesis, and biological evaluation of hydroquinone derivatives as novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase

Hydroquinones with Conformationally Constrained Substituents: Synthesis, Characterization, and Evaluation as Calcium–ATPase Inhibitors

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