Identification of Novel Human 15-Lipoxygenase-2 (h15-LOX-2) Inhibitors Using a Virtual Screening Approach.

The human 15-lipoxygenase-2 (h15-LOX-2) catalyzes mainly the regio- and stereospecific oxygenation of arachidonate to its corresponding hydroperoxide (15()-HpETE). h15-LOX-2 is implicated in the biosynthesis of inflammatory lipid mediators and plays a role in the development of atherosclerotic plaques, but it is still underexploited as a drug target. Here, to search for novel h15-LOX-2 inhibitors, we used a virtual screening (VS) approach consisting of shape-based matching, two-dimensional (2D) structural "dissimilarity", docking, and visual inspection filters, which were applied to a "curated" ZINC database (∼8 × 10 compounds).

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and begins with the uptake of the Sec carrier, selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP is metabolized via selenocysteine lyase (SCLY), producing selenide, a substrate for selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor, selenophosphate (HSePO), for the biosynthesis of the Sec-tRNA. Here, we discovered an alternative pathway in Sec metabolism mediated by peroxiredoxin 6 (PRDX6), independent of SCLY.

On the binding of auranofin to Prdx6 and its potential role in cancer cell sensitivity to treatment.

In this study, we demonstrate that ferroptosis is a component of the cell death mechanism induced by auranofin in HT-1080 cells, in contrast to the gold(III) compounds [Au(phen)Cl]PF and [Au(bnpy)Cl]. Additionally, we identify a potential role of Prdx6 in modulating the sensitivity of A-375 cells to auranofin treatment, whereas the gold(III) compounds evaluated here exhibit Prdx6-independent cytotoxicity. Finally, using mass spectrometry, we show that auranofin binds selectively to the catalytic Cys47 residue of Prdx6 in vitro under acidic conditions.

A Hybrid Approach Combining Shape-Based and Docking Methods to Identify Novel Potential P2X7 Antagonists from Natural Product Databases.

P2X7 is an ATP-activated purinergic receptor implicated in pro-inflammatory responses. It is associated with the development of several diseases, including inflammatory and neurodegenerative conditions. Although several P2X7 receptor antagonists have recently been reported in the literature, none of them is approved for clinical use.

Molecular Dynamics Simulations of the Human Ecto-5'-Nucleotidase (h-ecto-5'-NT, CD73): Insights into Protein Flexibility and Binding Site Dynamics.

Human ecto-5'-nucleotidase (h-ecto-5'-NT, CD73) is a homodimeric Zn-binding metallophosphoesterase that hydrolyzes adenosine 5'-monophosphate (5'-AMP) to adenosine and phosphate. h-Ecto-5'-NT is a key enzyme in purinergic signaling pathways and has been recognized as a promising biological target for several diseases, including cancer and inflammatory, infectious, and autoimmune diseases. Despite its importance as a biological target, little is known about h-ecto-5'-NT dynamics, which poses a considerable challenge to the design of inhibitors of this target enzyme.

Electrophilic oxysterols: generation, measurement and protein modification.

Cholesterol is an essential component of mammalian plasma membranes. Alterations in sterol metabolism or oxidation have been linked to various pathological conditions, including cardiovascular diseases, cancer, and neurodegenerative disorders. Unsaturated sterols are vulnerable to oxidation induced by singlet oxygen and other reactive oxygen species.

Lipid aldehyde hydrophobicity affects apo-SOD1 modification and aggregation.

Unsaturated lipids are oxidized by reactive oxygen species and enzymes, leading to the increased formation of lipid hydroperoxides and several electrophilic products. Lipid-derived electrophiles can modify macromolecules, such as proteins, resulting in the loss of function and/or aggregation. The accumulation of Cu,Zn-superoxide dismutase (SOD1) aggregates has been associated with familial cases of amyotrophic lateral sclerosis (ALS).

Virtual Screening Approach for the Identification of Hydroxamic Acids as Novel Human Ecto-5'-Nucleotidase Inhibitors.

Ecto-5'-nucleotidase (ecto-5'-NT, CD73) is a zinc-binding metallophosphatase that plays a key role in extracellular purinergic pathways, being implicated in several physiological and pathophysiological processes, such as immune homeostasis, inflammation, and tumor progression. As such, it has been recognized as a promising biological target for many diseases, including cancer, infections, and autoimmune diseases. Despite its importance, so far only a few inhibitors of this target enzyme are known, most of which are not suitable as drug candidates.

Be Aware of Aggregators in the Search for Potential Human -5'-Nucleotidase Inhibitors.

Promiscuous inhibition due to aggregate formation has been recognized as a major concern in drug discovery campaigns. Here, we report some aggregators identified in a virtual screening (VS) protocol to search for inhibitors of human -5'-nucleotidase (-5'-NT/CD73), a promising target for several diseases and pathophysiological events, including cancer, inflammation and autoimmune diseases. Four compounds (, , and ), selected from the ZINC-11 database, showed IC values in the micromolar range, being at the same time computationally predicted as potential aggregators.