The Resource Description Framework (RDF), together with well-defined ontologies, significantly increases data interoperability and usability. The SPARQL query language was introduced to retrieve requested RDF data and to explore links between them. Among other useful features, SPARQL supports federated queries that combine multiple independent data source endpoints. This allows users to obtain insights that are not possible using only a single data source. Owing to all of these useful features, many biological and chemical databases present their data in RDF, and support SPARQL querying. In our project, we primary focused on PubChem, ChEMBL and ChEBI small-molecule datasets. These datasets are already being exported to RDF by their creators. However, none of them has an official and currently supported SPARQL endpoint. This omission makes it difficult to construct complex or federated queries that could access all of the datasets, thus underutilising the main advantage of the availability of RDF data. Our goal is to address this gap by integrating the datasets into one database called the Integrated Database of Small Molecules (IDSM) that will be accessible through a SPARQL endpoint. Beyond that, we will also focus on increasing mutual interoperability of the datasets. To realise the endpoint, we decided to implement an in-house developed SPARQL engine based on the PostgreSQL relational database for data storage. In our approach, data are stored in the traditional relational form, and the SPARQL engine translates incoming SPARQL queries into equivalent SQL queries. An important feature of the engine is that it optimises the resulting SQL queries. Together with optimisations performed by PostgreSQL, this allows efficient evaluations of SPARQL queries. The endpoint provides not only querying in the dataset, but also the compound substructure and similarity search supported by our Sachem project. Although the endpoint is accessible from an internet browser, it is mainly intended to be used for programmatic access by other services, for example as a part of federated queries. For regular users, we offer a rich web application called ChemWebRDF using the endpoint. The application is publicly available at https://idsm.elixir-czech.cz/chemweb/ .

• Klíčová slova
• Resource Descriptor Framework, SPARQL, Small-molecule datasets,
• Publikační typ
• časopisecké články MeSH

Pluripotent stem cells of the bone marrow are stimulated by different cytokines to proliferation and differentiation into various types of blood cells. These cytokines are mostly glycoproteins. Erythropoietin stimulates stem cells to the formation of erythrocytes while colony-stimulating factors cause the formation of different types of white blood cells. Stem cell factors play an important role in the maintenance and survival of blood cells of all types. Thrombopoietin stimulates stem cells to proliferation and formation of blood platelets. Granulocyte colony-stimulating factor is probably the most important drug in use. It stimulates stem cells to the formation of neutrophile granulocytes. It is often used in recombinant forms such as filgrastim in the treatment of neutropenia in cancer chemotherapy or AIDS. Its pegylated conjugates such as pegfilgrastim are also available. Its activity can be supported by plerixafor, a small molecule - bicyclam derivative acting as an indirect agonist of stem cells factor. It acts as an antagonist of CXCR4 receptor activation of which brakes hematopoiesis. The treatment of conditions accompanied by thrombocytopenia such as idiopathic thrombocytopenic purpura is currently not performed by thrombopoietin but synthetic agonists of its receptor are preferred. Romiplostim is a peptibody. It consists of a protein part interacting with the thrombopoietin receptor which is, however, different from thrombopoietin, and of Fc fragment of immunoglobulin G1. In contrast, small molecule thrombopoietin receptor agonists represented by eltrombopag can be given orally unlike all of the above.

• Klíčová slova
• Colony-stimulating factors, eltrombopag., pegylation, plerixafor, romiplostim, stem-cell factors, thrombopoietin,
• MeSH
• benzoáty chemie   farmakologie   MeSH
• buněčná diferenciace účinky léků   MeSH
• faktory stimulující kolonie farmakologie   MeSH
• hydraziny chemie   farmakologie   MeSH
• knihovny malých molekul chemie   farmakologie   MeSH
• leukocyty mononukleární cytologie   účinky léků   metabolismus   MeSH
• lidé MeSH
• pyrazoly chemie   farmakologie   MeSH
• receptory thrombopoetinu agonisté   metabolismus   MeSH
• růstový faktor kmenových buněk farmakologie   MeSH
• trombocyty cytologie   metabolismus   MeSH
• trombopoéza účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• benzoáty MeSH
• eltrombopag MeSH Prohlížeč
• faktory stimulující kolonie MeSH
• hydraziny MeSH
• knihovny malých molekul MeSH
• pyrazoly MeSH
• receptory thrombopoetinu MeSH
• růstový faktor kmenových buněk MeSH

Intracellular protein aggregation causes proteotoxic stress, underlying highly debilitating neurodegenerative disorders in parallel with decreased proteasome activity. Nevertheless, under such stress conditions, the expression of proteasome subunits is upregulated by Nuclear Factor Erythroid 2-related factor 1 (NRF1), a transcription factor that is encoded by NFE2L1. Activating the NRF1 pathway could accordingly delay the onset of neurodegenerative and other disorders with impaired cell proteostasis. Here, we present a series of small-molecule compounds based on bis(phenylmethylen)cycloalkanones and their heterocyclic analogues, identified via targeted library screening, that can induce NRF1-dependent downstream events, such as proteasome synthesis, heat shock response, and autophagy, in both model cell lines and Caenorhabditis elegans strains. These compounds increase proteasome activity and decrease the size and number of protein aggregates without causing any cellular stress or inhibiting the ubiquitin-proteasome system (UPS). Therefore, our compounds represent a new promising therapeutic approach for various protein conformational diseases, including the most debilitating neurodegenerative diseases.

• Klíčová slova
• DDI2, NGLY1, NRF1(NFE2L1), Proteasome, Protein aggregates, Small molecules,
• MeSH
• aktivace transkripce účinky léků   MeSH
• autofagie účinky léků   MeSH
• Caenorhabditis elegans * účinky léků   metabolismus   MeSH
• faktor 1 související s NF-E2 metabolismus   genetika   MeSH
• knihovny malých molekul farmakologie   MeSH
• lidé MeSH
• patologická konformace proteinů metabolismus   farmakoterapie   MeSH
• proteasomový endopeptidasový komplex * metabolismus   MeSH
• proteinové agregáty * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• faktor 1 související s NF-E2 MeSH
• knihovny malých molekul MeSH
• proteasomový endopeptidasový komplex * MeSH
• proteinové agregáty * MeSH

Elastin, a key structural protein essential for the elasticity of the skin and elastogenic tissues, degrades with age. Replenishing elastin holds promise for anti-aging cosmetics and the supplementation of elastic activities of the cardiovascular system. We employed RiboScreenTM, a technology for identifying molecules that enhance the production of specific proteins, to target the production of tropoelastin. We make use of RiboScreenTM in two crucial steps: first, to pinpoint a target ribosomal protein (TRP), which acts as a switch to increase the production of the protein of interest (POI), and second, to identify small molecules that activate this ribosomal protein switch. Using RiboScreenTM, we identified ribosomal protein L40, henceforth eL40, as a TRP switch to boost tropoelastin production. Drug discovery identified a small-molecule hit that binds to eL40. In-cell treatment demonstrated activity of the eL40 ligand and delivered increased tropoelastin production levels in a dose-dependent manner. Thus, we demonstrate that RiboScreenTM can successfully identify a small-molecule hit capable of selectively enhancing tropoelastin production. This compound has the potential to be developed for topical or systemic applications to promote skin rejuvenation and to supplement elastic functionality within the cardiovascular system.

• Klíčová slova
• RiboScreenTM Technology, ageing of elastic tissues, customized protein expression, elastin, ribosomal protein eL40, small-molecule hit, tropoelastin expression,
• MeSH
• elastin * metabolismus   genetika   MeSH
• knihovny malých molekul farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• ribozomální proteiny * metabolismus   genetika   MeSH
• ribozomy * metabolismus   účinky léků   MeSH
• tropoelastin * metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• elastin * MeSH
• knihovny malých molekul MeSH
• ligandy MeSH
• ribozomální proteiny * MeSH
• tropoelastin * MeSH

Autophagy is a catabolic process that was described to play a critical role in advanced stages of cancer, wherein it maintains tumor cell homeostasis and growth by supplying nutrients. Autophagy is also described to support alternative cellular trafficking pathways, providing a non-canonical autophagy-dependent inflammatory cytokine secretion mechanism. Therefore, autophagy inhibitors have high potential in the treatment of cancer and acute inflammation. In our study, we identified compound 1 as an inhibitor of the ATG12-ATG3 protein-protein interaction. We focused on the systematic modification of the original hit 1, a casein kinase 2 (CK2) inhibitor, to find potent disruptors of ATG12-ATG3 protein-protein interaction. A systematic modification of the hit structure led us to a wide plethora of compounds that maintain its ATG12-ATG3 inhibitory activity, which could act as a viable starting point to design new compounds with diverse therapeutic applications.

• Klíčová slova
• Autophagy, Autophagy inhibition, Protein–protein interaction, Small molecule,
• MeSH
• autofagie účinky léků   MeSH
• kaseinkinasa II antagonisté a inhibitory   metabolismus   MeSH
• knihovny malých molekul * chemie   farmakologie   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• proteiny spojené s autofagií * metabolismus   antagonisté a inhibitory   MeSH
• vazba proteinů MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kaseinkinasa II MeSH
• knihovny malých molekul * MeSH
• proteiny spojené s autofagií * MeSH

INTRODUCTION: Interleukin-17A (IL-17A) is a well-established pro-inflammatory cytokine, which plays a pivotal role in immune and autoimmune diseases including psoriasis, asthma, psoriatic arthritis, and rheumatoid arthritis. Three currently approved monoclonal antibodies (mAbs) are in clinical practice for the treatment of multiple immune diseases. However, the disadvantages of the mAbs, such as non-oral administration, poor tissue penetration, lacking blood-brain barrier penetration, often long half-life times, narrow its application. Thus, intensive research is performed to discover potent small molecules, peptides, and macrocycles targeting the IL-17A/IL-17 RA protein-protein interaction (PPI) to modulate immune responses as an attractive approach for immunotherapy. AREAS COVERED: Small molecules, macrocycles, and peptides targeting IL-17A/IL-17RA PPI from 2013 to 2021. EXPERT OPINION: The rapid increase in the identification of small-molecule inhibitors of IL-17 should translate into a supplement of current biotherapeutics with mAbs. Potential advantages of small molecules over mAbs show room for clinical treatment improvement and new indication areas . An increasing number of patents and articles are recently published on small-molecule immunomodulators (SMIMs). Two compounds from Lilly and Leo Pharma are currently investigated in early clinical trials, followed by a Dice molecule. The outcome of these trials will influence future development of IL-17 inhibitors for treatment of inflammation-related diseases.

• Klíčová slova
• IL17A, antagonist, drug, inflammation, macrocycle, small molecule,
• MeSH
• interleukin-17 * MeSH
• lidé MeSH
• patenty jako téma * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• interleukin-17 * MeSH

Ischemia/reperfusion (I/R) injury is mediated in large part by opening of the mitochondrial permeability transition pore (PTP). Consequently, inhibitors of the PTP hold great promise for the treatment of a variety of cardiovascular disorders. At present, PTP inhibition is obtained only through the use of drugs (e.g. cyclosporine A, CsA) targeting cyclophilin D (CyPD) which is a key modulator, but not a structural component of the PTP. This limitation might explain controversial findings in clinical studies. Therefore, we investigated the protective effects against I/R injury of small-molecule inhibitors of the PTP (63 and TR002) that do not target CyPD. Both compounds exhibited a dose-dependent inhibition of PTP opening in isolated mitochondria and were more potent than CsA. Notably, PTP inhibition was observed also in mitochondria devoid of CyPD. Compounds 63 and TR002 prevented PTP opening and mitochondrial depolarization induced by Ca2+ overload and by reactive oxygen species in neonatal rat ventricular myocytes (NRVMs). Remarkably, both compounds prevented cell death, contractile dysfunction and sarcomeric derangement induced by anoxia/reoxygenation injury in NRVMs at sub-micromolar concentrations, and were more potent than CsA. Cardioprotection was observed also in adult mouse ventricular myocytes and human iPSc-derived cardiomyocytes, as well as ex vivo in perfused hearts. Thus, this study demonstrates that 63 and TR002 represent novel cardioprotective agents that inhibit PTP opening independent of CyPD targeting.

• Klíčová slova
• Caffeine (PubChem CID: 2519), Calcimycin (PubChem CID: 40486), Cardiomyocytes, Cardioprotection, Compound 63 (PubChem CID: 75204518), Cyclosporine A (PubChem CID: 5284373), Ischemia, MitoParaquat (PubChem CID: 129909777), Mitochondria, Permeability transition, Reperfusion,
• MeSH
• buněčné linie MeSH
• kardiomyocyty účinky léků   MeSH
• kardiotonika farmakologie   terapeutické užití   MeSH
• knihovny malých molekul farmakologie   terapeutické užití   MeSH
• kultivované buňky MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• potkani Sprague-Dawley MeSH
• potkani Wistar MeSH
• přechodový pór mitochondriální permeability antagonisté a inhibitory   metabolismus   MeSH
• reperfuzní poškození myokardu farmakoterapie   metabolismus   patologie   MeSH
• srdeční mitochondrie účinky léků   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• kardiotonika MeSH
• knihovny malých molekul MeSH
• přechodový pór mitochondriální permeability MeSH

BACKGROUND: Analyte annotation confidence in untargeted liquid chromatography mass-spectrometry (LC-MS) based chemical analysis can be enhanced by leveraging retention time information. For this, the chromatographic characteristics of the analytical system used should be well characterized. In this study, we measured 604 diverse chemical standards to characterize a dual LC setup consisting of pentabromobenzyl (PBr) and type-C silica hydride (SiH) columns operating in reversed-phase (RP) and aqueous normal-phase (ANP) mode, respectively. RESULTS: ANP and RP separations individually retained 40 % and 64 % of standards in cLogP range from -6.60 to 8.67 and -3.34 to 12.95, respectively. Using both columns, the coverage increased to 79 % of standards with cLogP range from -6.60 to 12.95 (median cLogP = 1.63). Retention selectivity follows the number of basic nitrogen atoms in the molecule on SiH column and polarity (cLogP) on PBr column. Column repeatability and reproducibility were tested in triplicate using a chemically diverse subset of 108 standards. Repeatability of retention times, peak widths and peak areas was 0.3 %, 14 %, 4 % for SiH column and 0.2 %, 12 %, 4 % for PBr column. Similarly, reproducibility was 15 %, 34 %, 30 % for SiH column and 9 %, 18 % and 34 % for PBr column. Predictive RT models were developed based on experimental RT data, achieving R2 values of 0.92 and 0.96, with mean absolute errors of 0.29 min and 0.27 min for SiH and PBr columns, respectively. SIGNIFICANCE: As proof of concept, 129 metabolites were annotated in pooled human serum and plasma by matching standard or predicted RT on one or both columns. The RT models and MS2 spectra of standards are openly available, facilitating uptake of this well-characterized chromatographic system to increase confidence in analyte annotation.

• Klíčová slova
• Aqueous normal-phase, Chemicals, Exposome, Metabolomics, Non-targeted, Retention time prediction,
• MeSH
• chromatografie kapalinová MeSH
• hmotnostní spektrometrie * MeSH
• knihovny malých molekul * MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• knihovny malých molekul * MeSH

The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds are emerging as an attractive alternative that can potentially overcome the drawbacks of mAb-based therapy. In this article, we present a novel class of small molecule compounds based on the terphenyl scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an m-terphenyl core, an additional aromatic ring, and a solubilizing agent. Using molecular docking, we designed a series of final compounds, which were subsequently synthesized and tested in HTRF assay and NMR binding assay to evaluate their activity. In addition, we performed an in-depth analysis of the mutual arrangement of the phenyl rings of the terphenyl core within the binding pocket of PD-L1 and found several correlations between the plane angle values and the affinity of the compounds towards the protein.

• Klíčová slova
• C2-symmetrical ligands, PD-L1, cancer, immune checkpoint, small molecule inhibitor,
• MeSH
• antigeny CD274 * antagonisté a inhibitory   metabolismus   chemie   MeSH
• antigeny CD279 * antagonisté a inhibitory   metabolismus   chemie   MeSH
• inhibitory kontrolních bodů chemie   farmakologie   MeSH
• knihovny malých molekul farmakologie   chemie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• simulace molekulového dockingu * MeSH
• terfenylové sloučeniny * chemie   farmakologie   MeSH
• vazba proteinů * MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD274 * MeSH
• antigeny CD279 * MeSH
• CD274 protein, human MeSH Prohlížeč
• inhibitory kontrolních bodů MeSH
• knihovny malých molekul MeSH
• PDCD1 protein, human MeSH Prohlížeč
• terfenylové sloučeniny * MeSH

By binding to the spliceosomal protein Snu66, the human ubiquitin-like protein Hub1 is a modulator of the spliceosome performance and facilitates alternative splicing. Small molecules that bind to Hub1 would be of interest to study the protein-protein interaction of Hub1/Snu66, which is linked to several human pathologies, such as hypercholesterolemia, premature aging, neurodegenerative diseases, and cancer. To identify small molecule ligands for Hub1, we used the interface analysis, peptide modeling of the Hub1/Snu66 interaction and the fragment-based NMR screening. Fragment-based NMR screening has not proven sufficient to unambiguously search for fragments that bind to the Hub1 protein. This was because the Snu66 binding pocket of Hub1 is occupied by pH-sensitive residues, making it difficult to distinguish between pH-induced NMR shifts and actual binding events. The NMR analyses were therefore verified experimentally by microscale thermophoresis and by NMR pH titration experiments. Our study found two small peptides that showed binding to Hub1. These peptides are the first small-molecule ligands reported to interact with the Hub1 protein.

• Klíčová slova
• anti-cancer therapy, nuclear magnetic resonance, protein-peptide docking, protein-protein interactions, small-molecule inhibitors,
• MeSH
• alternativní sestřih * MeSH
• lidé MeSH
• ligandy MeSH
• magnetická rezonanční spektroskopie MeSH
• počítače MeSH
• spliceozomy * metabolismus   MeSH
• ubikvitiny genetika   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ligandy MeSH
• ubikvitiny MeSH