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

Aspartate transcarbamoylase (ATC) is the first committed step in de novo pyrimidine biosynthesis in eukaryotes and plants. A potent transition state analog of human ATCase (PALA) has previously been assessed in clinical trials for the treatment of cancer, but was ultimately unsuccessful. Additionally, inhibition of this pathway has been proposed to be a target to suppress cell proliferation in E. coli, the malarial parasite and tuberculosis. In this manuscript we screened a 70-member library of ATC inhibitors developed against the malarial and tubercular ATCases for inhibitors of the human ATC. Four compounds showed low nanomolar inhibition (IC50 30-120 nM) in an in vitro activity assay. These compounds significantly outperform PALA, which has a triphasic inhibition response under identical conditions, in which significant activity remains at PALA concentrations above 10 μM. Evidence for a druggable allosteric pocket in human ATC is provided by both in vitro enzyme kinetic, homology modeling and in silico docking. These compounds also suppress the proliferation of U2OS osteoblastoma cells by promoting cell cycle arrest in G0/G1 phase. This report provides the first evidence for an allosteric pocket in human ATC, which greatly enhances its druggability and demonstrates the potential of this series in cancer therapy.

• Klíčová slova
• Aspartate Transcarbamoylase, Molecular Docking, Non-competitive Inhibition, Osteosarcoma, Pyrimidine Biosynthesis,
• MeSH
• alosterická regulace účinky léků   MeSH
• antitumorózní látky farmakologie   chemie   chemická syntéza   MeSH
• aspartátkarbamoyltransferasa * antagonisté a inhibitory   metabolismus   chemie   MeSH
• epitelové buňky účinky léků   metabolismus   MeSH
• inhibitory enzymů * farmakologie   chemie   chemická syntéza   MeSH
• knihovny malých molekul chemie   farmakologie   chemická syntéza   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• nádory kostí farmakoterapie   patologie   metabolismus   MeSH
• osteosarkom * farmakoterapie   patologie   metabolismus   MeSH
• proliferace buněk * účinky léků   MeSH
• simulace molekulového dockingu 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
• antitumorózní látky MeSH
• aspartátkarbamoyltransferasa * MeSH
• inhibitory enzymů * MeSH
• 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

The binding process of insulin to its transmembrane receptor entails a sophisticated interplay between two proteins, each possessing two binding sites. Given the difficulties associated with the use of insulin in the treatment of diabetes, despite its remarkable efficacy, there is interest in smaller and more stable compounds than the native hormone that would effectively activate the receptor. Our study adopts a strategy focused on synthesizing extensive combinatorial libraries of bipodal compounds consisting of two distinct peptides linked to a molecular scaffold. These constructs, evaluated in a resin bead-bound format, were designed to assess their binding to the insulin receptor. Despite notable nonspecific binding, our approach successfully generated and tested millions of compounds. Rigorous evaluations via flow cytometry and specific antibodies revealed peptide sequences with specific interactions at either receptor binding Site 1 or 2. Notably, these sequences bear similarity to peptides discovered through phage display by other researchers. This convergence of chemical and biological methods underscores nature's beauty, revealing general principles in peptide binding to the insulin receptor. Overall, our study deepens the understanding of molecular interactions in ligand binding to the insulin receptor, highlighting the challenges of targeting large proteins with small synthetic peptides.

• Klíčová slova
• insulin, library, peptide, receptor, scaffold,
• MeSH
• inzulin metabolismus   chemie   MeSH
• knihovny malých molekul chemie   farmakologie   chemická syntéza   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• peptidová knihovna MeSH
• peptidy chemie   metabolismus   chemická syntéza   MeSH
• receptor inzulinu * metabolismus   chemie   MeSH
• techniky kombinatorické chemie * MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inzulin MeSH
• knihovny malých molekul MeSH
• ligandy MeSH
• peptidová knihovna MeSH
• peptidy MeSH
• receptor inzulinu * 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
• faktor růstu kmenových buněk farmakologie   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
• 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
• faktor růstu kmenových buněk MeSH
• faktory stimulující kolonie MeSH
• hydraziny MeSH
• knihovny malých molekul MeSH
• pyrazoly MeSH
• receptory thrombopoetinu MeSH

Causing approximately 10 million incident cases and 1.3-1.5 million deaths every year, Mycobacterium tuberculosis remains a global health problem. The risk is further exacerbated with latent tuberculosis (TB) infection, the HIV pandemic, and increasing anti-TB drug resistance. Therefore, unexplored chemical scaffolds directed towards new molecular targets are increasingly desired. In this context, mycobacterial energy metabolism, particularly the oxidative phosphorylation (OP) pathway, is gaining importance. Mycobacteria possess primary dehydrogenases to fuel electron transport; aa3-type cytochrome c oxidase and bd-type menaquinol oxidase to generate a protonmotive force; and ATP synthase, which is essential for both growing mycobacteria as well as dormant mycobacteria because ATP is produced under both aerobic and hypoxic conditions. Small organic molecules targeting OP are active against latent TB as well as resistant TB strains. FDA approval of the ATP synthase inhibitor bedaquiline and the discovery of clinical candidate Q203, which both interfere with the cytochrome bc1 complex, have already confirmed mycobacterial energy metabolism to be a valuable anti-TB drug target. This review highlights both preferable molecular targets within mycobacterial OP and promising small organic molecules targeting OP. Progressive research in the area of mycobacterial OP revealed several highly potent anti-TB compounds with nanomolar-range MICs as low as 0.004 μM against Mtb H37Rv. Therefore, we are convinced that targeting the OP pathway can combat resistant TB and latent TB, leading to more efficient anti-TB chemotherapy.

• Klíčová slova
• ATP synthase, Inhibitors, Mycobacterium tuberculosis, Oxidative phosphorylation, QcrB,
• MeSH
• antituberkulotika chemie   farmakologie   MeSH
• energetický metabolismus MeSH
• knihovny malých molekul chemie   farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   metabolismus   MeSH
• organické látky chemie   farmakologie   MeSH
• tuberkulóza farmakoterapie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antituberkulotika MeSH
• knihovny malých molekul MeSH
• organické látky MeSH

Skin sensitization potential or potency is an important end point in the safety assessment of new chemicals and new chemical mixtures. Formerly, animal experiments such as the local lymph node assay (LLNA) were the main form of assessment. Today, however, the focus lies on the development of nonanimal testing approaches (i.e., in vitro and in chemico assays) and computational models. In this work, we investigate, based on publicly available LLNA data, the ability of aggregated, Mondrian conformal prediction classifiers to differentiate between non- sensitizing and sensitizing compounds as well as between two levels of skin sensitization potential (weak to moderate sensitizers, and strong to extreme sensitizers). The advantage of the conformal prediction framework over other modeling approaches is that it assigns compounds to activity classes only if a defined minimum level of confidence is reached for the individual predictions. This eliminates the need for applicability domain criteria that often are arbitrary in their nature and less flexible. Our new binary classifier, named Skin Doctor CP, differentiates nonsensitizers from sensitizers with a higher reliability-to-efficiency ratio than the corresponding nonconformal prediction workflow that we presented earlier. When tested on a set of 257 compounds at the significance levels of 0.10 and 0.30, the model reached an efficiency of 0.49 and 0.92, and an accuracy of 0.83 and 0.75, respectively. In addition, we developed a ternary classification workflow to differentiate nonsensitizers, weak to moderate sensitizers, and strong to extreme sensitizers. Although this model achieved satisfactory overall performance (accuracies of 0.90 and 0.73, and efficiencies of 0.42 and 0.90, at significance levels 0.10 and 0.30, respectively), it did not obtain satisfying class-wise results (at a significance level of 0.30, the validities obtained for nonsensitizers, weak to moderate sensitizers, and strong to extreme sensitizers were 0.70, 0.58, and 0.63, respectively). We argue that the model is, in consequence, unable to reliably identify strong to extreme sensitizers and suggest that other ternary models derived from the currently accessible LLNA data might suffer from the same problem. Skin Doctor CP is available via a public web service at https://nerdd.zbh.uni-hamburg.de/skinDoctorII/.

• MeSH
• databáze faktografické MeSH
• knihovny malých molekul chemie   farmakologie   MeSH
• kožní testy * MeSH
• kůže účinky léků   MeSH
• molekulární struktura MeSH
• myši MeSH
• organické látky chemie   farmakologie   MeSH
• test regionální lymfatické uzliny MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• knihovny malých molekul MeSH
• organické látky MeSH

DNA-encoded chemical libraries (DECLs) are powerful tools for modern drug discovery. A DECL is a pooled mixture of small molecule compounds, each of which is tagged with a unique DNA sequence which functions as a barcode. After incubation with a drug target and washing to remove non-binders, the bound molecules are eluted and submitted for DNA sequencing to determine which molecules are binding the target. While the DECL technology itself is ultra-high throughput, the following re-synthesis of identified compounds for orthogonal validation experiments remains the bottleneck. Using existing DNA-small molecule conjugates directly for affinity measurements, as opposed to complete compound resynthesis, could accelerate the discovery process. To this end, we have tested various geometries of fluorescently-labelled DNA constructs for fluorescence anisotropy (FA) experiments. Minimizing the distance between the fluorescent moiety and ligand can maximize the correlation between ligand-protein interaction and corresponding change in fluorophore rotational freedom, thus leading to larger, easier to interpret changes in FA values. However, close proximity can also cause artifacts due to potentially promiscuous interactions between fluorophore and protein. By balancing these two opposite effects, we have identified applicable fluorescently labelled DNA constructs displaying either a single ligand or pairs of fragments for affinity measurement using a FA assay.

• Klíčová slova
• DNA-Encoded chemical library, Drug discovery, Fluorescence anisotropy, Hit validation, Small molecules,
• MeSH
• DNA chemická syntéza   chemie   MeSH
• fluorescenční barviva chemická syntéza   chemie   MeSH
• fluorescenční polarizace MeSH
• knihovny malých molekul chemická syntéza   chemie   farmakologie   MeSH
• ligandy MeSH
• objevování léků MeSH
• preklinické hodnocení léčiv MeSH
• techniky kombinatorické chemie MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• fluorescenční barviva MeSH
• knihovny malých molekul MeSH
• ligandy MeSH

The compounds from eight different thiazolidine and thiazole series were assessed as potential antileishmanial scaffolds. They were tested for antileishmanial activity against promastigotes of Leishmania major using in vitro primary screen and dose response assays. The compounds from six thiazolidine and thiazole series were identified as the hits with antileishmanial activity against L. major. However, the analyses of structure-activity relations (SARs) showed that the interpretable SARs were obtained only for phenyl-indole hybrids (compounds C1, C2, C3 and C5) as the most effective compounds against L. major promastigotes (IC50 < 10 µM) with low toxicity to human fibroblasts. For the scaffold of these compounds, the most significant SAR patterns were: free N3 position of thiazolidinone core, absence of big fragments at the C5 position of thiazolidinone core and presence of halogen atoms or nitro group in the phenyl ring of phenyl-indole fragment. As previous studies showed that these compounds also have activity against the two Trypanosoma species, Trypanosoma brucei and Trypanosoma gambiense, their scaffold could be associated with a broader antiparasitic activity.

• Klíčová slova
• Antileishmanial activity, Indoles, SAR, Thiazole core, Thiazolidinone core,
• MeSH
• fibroblasty účinky léků   MeSH
• knihovny malých molekul chemie   farmakologie   toxicita   MeSH
• Leishmania major účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• parazitické testy citlivosti MeSH
• thiazolidiny chemie   farmakologie   toxicita   MeSH
• trypanocidální látky chemie   farmakologie   toxicita   MeSH
• Trypanosoma brucei brucei účinky léků   MeSH
• Trypanosoma brucei gambiense účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• knihovny malých molekul MeSH
• thiazolidiny MeSH
• trypanocidální látky MeSH

The goal of this study was to develop novel radioprotective agents targeting the intrinsic apoptotic pathway and thus decreasing the radiation-induced damage. For that purpose, we designed, synthesized and analyzed ten new compounds based on the 1-(4-(2-hydroxyethyl)piperazin-1-yl)-3-phenoxypropan-2-ol leading structure. The cytotoxicity of the newly synthesized substances was tested in vitro on cell lines derived from different progenitor cells by WST-1 proliferation assay. MTT test was utilized to assess half-maximal inhibitory concentrations and maximum tolerated concentrations of novel compounds in A-549 cells. Screening for radioprotective properties was performed using flow-cytometry in MOLT-4 cells exposed to 60Co ionizing gamma radiation. Selected candidates underwent in vivo testing in C57Bl/6 J mice having a positive impact on their immunological status. In summary, we report here promising compounds with radioprotective effect in vivo.

• Klíčová slova
• 1-(2-hydroxyethyl)piperazine derivative, In vitro, Ionizing radiation, Mice, Radioprotection, Synthesis,
• MeSH
• apoptóza účinky léků   MeSH
• knihovny malých molekul chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• propanoly chemická syntéza   chemie   farmakologie   MeSH
• radioprotektivní látky chemická syntéza   chemie   farmakologie   MeSH
• simulace molekulového dockingu MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• knihovny malých molekul MeSH
• propanoly MeSH
• radioprotektivní látky MeSH