Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening

Scarpino, Andrea; Bajusz, Dávid; Proj, Matic; Gobec, Stanislav; Sosič, Izidor; Ferenczy, György G.; Keserü, György M.

doi:10.3390/molecules24142590

Cited by 12 publications

(8 citation statements)

References 37 publications

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“…The CovDock-VS was used in a virtual-screening protocol to find covalent inhibitors of the immunoproteasome's 5i subunit [ 54 ]. A commercial library of 100,000 boronic acids with desirable characteristics was screened in a multi-step procedure.…”

Section: Covalent Docking With Covalent-docking Programs: Methods And...mentioning

confidence: 99%

Docking covalent targets for drug discovery: stimulating the computer-aided drug design community of possible pitfalls and erroneous practices

et al. 2022

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The continuous approval of covalent drugs in recent years for the treatment of diseases has led to an increased search for covalent agents by medicinal chemists and computational scientists worldwide. In the computational parlance, molecular docking which is a popular tool to investigate the interaction of a ligand and a protein target, does not account for the formation of covalent bond, and the increasing application of these conventional programs to covalent targets in early drug discovery practice is a matter of utmost concern. Thus, in this comprehensive review, we sought to educate the docking community about the realization of covalent docking and the existence of suitable programs to make their future virtual-screening events on covalent targets worthwhile and scientifically rational. More interestingly, we went beyond the classical description of the functionality of covalent-docking programs down to selecting the ‘best’ program to consult with during a virtual-screening campaign based on receptor class and covalent warhead chemistry. In addition, we made a highlight on how covalent docking could be achieved using random conventional docking software. And lastly, we raised an alert on the growing erroneous molecular docking practices with covalent targets. Our aim is to guide scientists in the rational docking pursuit when dealing with covalent targets, as this will reduce false-positive results and also increase the reliability of their work for translational research. Graphical abstract

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Section: Covalent Docking With Covalent-docking Programs: Methods And...mentioning

confidence: 99%

Docking covalent targets for drug discovery: stimulating the computer-aided drug design community of possible pitfalls and erroneous practices

et al. 2022

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“…181 Scarpino et al screened a large library of nonpeptidic boronic acid derivatives and identified compound 28 as a weak inhibitor of the immunoproteasome (IC 50 = 34 μM, Figure 9). 182 Further modification of this compound may provide a new generation of potent nonpeptidic proteasome inhibitors as chemotherapeutics. Similarly, Ladi et al designed compound 29 that showed remarkable in vitro activity against the β5 and β1 subunit of the immunoproteasome (β5i IC 50 = 4.1 nM; and β1i IC 50 = 0.85 nM).…”

Section: Peptide and Small Molecule Boronic Acids As Therapeuticsmentioning

confidence: 99%

The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology

Grams,

Santos,

Scorei

et al. 2024

Chem. Rev.

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Boron-containing compounds (BCC) have emerged as important pharmacophores. To date, five BCC drugs (including boronic acids and boroles) have been approved by the FDA for the treatment of cancer, infections, and atopic dermatitis, while some natural BCC are included in dietary supplements. Boron's Lewis acidity facilitates a mechanism of action via formation of reversible covalent bonds within the active site of target proteins. Boron has also been employed in the development of fluorophores, such as BODIPY for imaging, and in carboranes that are potential neutron capture therapy agents as well as novel agents in diagnostics and therapy. The utility of natural and synthetic BCC has become multifaceted, and the breadth of their applications continues to expand. This review covers the many uses and targets of boron in medicinal chemistry.

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“…Hits that were predicted to adopt a Ro19-like binding mode [105] were prioritized. Among the identified compounds, 1a (Figure 3; originally published as 1) is ranked the highest, as it shows modest affinity for β5i (IC 50 value for purified human iCP: 34 µM) and moderate selectivity over β5c (three-fold; Table 1) [85]. However, a complete cCP and iCP subunit selectivity profile has not been determined.…”

Section: • Boronatesmentioning

confidence: 99%

A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

Huber

Groll

2021

Cells

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At the heart of the ubiquitin–proteasome system, the 20S proteasome core particle (CP) breaks down the majority of intracellular proteins tagged for destruction. Thereby, the CP controls many cellular processes including cell cycle progression and cell signalling. Inhibitors of the CP can suppress these essential biological pathways, resulting in cytotoxicity, an effect that is beneficial for the treatment of certain blood cancer patients. During the last decade, several preclinical studies demonstrated that selective inhibition of the immunoproteasome (iCP), one of several CP variants in mammals, suppresses autoimmune diseases without inducing toxic side effects. These promising findings led to the identification of natural and synthetic iCP inhibitors with distinct chemical structures, varying potency and subunit selectivity. This review presents the most prominent iCP inhibitors with respect to possible scientific and medicinal applications, and discloses recent trends towards pan-immunoproteasome reactive inhibitors that cumulated in phase II clinical trials of the lead compound KZR-616 for chronic inflammations.

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Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening

Cited by 12 publications

References 37 publications

Docking covalent targets for drug discovery: stimulating the computer-aided drug design community of possible pitfalls and erroneous practices

Docking covalent targets for drug discovery: stimulating the computer-aided drug design community of possible pitfalls and erroneous practices

The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology

A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

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