6,653 results match your criteria low nanomolar

Repurposing proscillaridin A in combination with decitabine against embryonal rhabdomyosarcoma RD cells.

Cancer Chemother Pharmacol 2021 Jul 31. Epub 2021 Jul 31.

Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, QC, Canada.

Purpose: Embryonal rhabdomyosarcoma (eRMS) is the most common type of rhabdomyosarcoma in children. eRMS is characterized by malignant skeletal muscle cells driven by hyperactivation of several oncogenic pathways including the MYC pathway. Targeting MYC in cancer has been extremely challenging. Read More

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Rational design-aided discovery of novel 1,2,4-oxadiazole derivatives as potential EGFR inhibitors.

Bioorg Chem 2021 Jul 1;114:105124. Epub 2021 Jul 1.

Division of Biological & Life Sciences (Formerly Institute of Life Sciences), School of Arts & Sciences, Ahmedabad University, Navaragnpura, Ahmedabad 380009, Gujarat, India; National Institute of Animal Biotechnology, Near Gowlidoddy, Extended Q City Road, Gachibowli, Hyderabad 500032, Telangana, India.

A molecular dynamics-based sampling of epidermal growth factor receptor tyrosine kinase (EGFR-TK) was carried out to search for energetically more stable protein, which was then used for molecular docking of a series of 1,2,4-oxadiazole derivatives previously reported from our laboratory. A total of 14 compounds were docked, where compounds 6a and 6b showed better binding to EGFR in silico. Further, physicochemical properties of all the compounds were calculated, which suggested that all the molecules obeyed Lipinski's rule of 5 and had favorable polar surface area and CaCO2 permeability along with the low potential for HERG inhibition. Read More

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Characterizing the Low-Dose Effects of Methylmercury on the Early Stages of Embryo Development Using Cultured Human Embryonic Stem Cells.

Environ Health Perspect 2021 Jul 30;129(7):77007. Epub 2021 Jul 30.

Department of Biology, University of Ottawa, Ottawa, Ontario, Canada.

Background: Global concerns of methylmercury (MeHg) exposure have been raised, especially on its effects on pregnant women. Recent epidemiological studies have revealed associations between maternal blood/hair MeHg concentrations, adverse pregnancy outcomes, and developmental deficits. However, the underlying mechanisms remain unclear. Read More

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Preclinical evaluation of AFM24, a novel CD16A-specific innate immune cell engager targeting EGFR-positive tumors.

MAbs 2021 Jan-Dec;13(1):1950264

Research & Development, Affimed GmbH, Heidelberg, Germany.

Epidermal growth factor receptor (EGFR)-targeted cancer therapy such as anti-EGFR monoclonal antibodies and tyrosine kinase inhibitors have demonstrated clinical efficacy. However, there remains a medical need addressing limitations of these therapies, which include a narrow therapeutic window mainly due to skin and organ toxicity, and primary and secondary resistance mechanisms of the EGFR-signaling cascade (e.g. Read More

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Molecular Plasticity of Crystalline CK2α' Leads to KN2, a Bivalent Inhibitor of Protein Kinase CK2 with Extraordinary Selectivity.

J Med Chem 2021 Jul 29. Epub 2021 Jul 29.

Department für Chemie, Institut für Biochemie, Universität zu Köln, Zülpicher Str. 47, D-50674 Köln, Germany.

CK2α and CK2α' are paralogous catalytic subunits of CK2, which belongs to the eukaryotic protein kinases. CK2 promotes tumorigenesis and the spread of pathogenic viruses like SARS-CoV-2 and is thus an attractive drug target. Efforts to develop selective CK2 inhibitors binding offside the ATP site had disclosed the αD pocket in CK2α; its occupation requires large conformational adaptations of the helix αD. Read More

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Silicon compounds in carbon-11 radiochemistry: present use and future perspectives.

Org Biomol Chem 2021 Jul 28. Epub 2021 Jul 28.

School of Biomedical Engineering and Imaging Sciences, 4th floor Lambeth Wing, St Thomas' Hospital, King's College London, London SE1 7EH, UK.

Positron emission tomography (PET) is a powerful functional imaging technique that requires the use of positron emitting nuclides. Carbon-11 (11C) radionuclide has several advantages related to the ubiquity of carbon atoms in biomolecules and the conservation of pharmacological properties of the molecule upon isotopic exchange of carbon-12 with carbon-11. However, due to the short half-life of 11C (20. Read More

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A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H Receptor.

J Med Chem 2021 Jul 26. Epub 2021 Jul 26.

Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, Regensburg 93053, Germany.

The histamine H receptor (HR) is considered an attractive drug target for various neurological diseases. We here report the synthesis of UR-NR266, a novel fluorescent HR ligand. Broad pharmacological characterization revealed UR-NR266 as a sub-nanomolar compound at the HR with an exceptional selectivity profile within the histamine receptor family. Read More

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Biphenyl substituted lysine derivatives as recognition elements for the matrix metalloproteinases MMP-2 and MMP-9.

Bioorg Chem 2021 Jul 9;115:105155. Epub 2021 Jul 9.

Dipartimento di Chimica e Chimica Industriale, Via Giuseppe Moruzzi, 13, 56124 Pisa, Italy.

Matrix metalloproteinases (MMPs) are an important factor in cancer progression and metastasis, especially gelatinases MMP-2 and MMP-9. A simple methodology for their detection and monitoring is highly desirable. Molecular probes have been very widely and successfully applied to study the activity of MMPs in cellular processes in vitro. Read More

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Crystal Structure-Guided Design of Bisubstrate Inhibitors and Photoluminescent Probes for Protein Kinases of the PIM Family.

Molecules 2021 Jul 19;26(14). Epub 2021 Jul 19.

Institute of Chemistry, University of Tartu, 14A Ravila St., 50411 Tartu, Estonia.

We performed an X-ray crystallographic study of complexes of protein kinase PIM-1 with three inhibitors comprising an adenosine mimetic moiety, a linker, and a peptide-mimetic (d-Arg) fragment. Guided by the structural models, simplified chemical structures with a reduced number of polar groups and chiral centers were designed. The developed inhibitors retained low-nanomolar potency and possessed remarkable selectivity toward the PIM kinases. Read More

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Association of clusterin with the BRI2-derived amyloid molecules ABri and ADan.

Neurobiol Dis 2021 Jul 21;158:105452. Epub 2021 Jul 21.

Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. Electronic address:

Familial British and Danish dementias (FBD and FDD) share striking neuropathological similarities with Alzheimer's disease (AD), including intraneuronal neurofibrillary tangles as well as parenchymal and vascular amyloid deposits. Multiple amyloid associated proteins with still controversial role in amyloidogenesis colocalize with the structurally different amyloid peptides ABri in FBD, ADan in FDD, and Aβ in AD. Genetic variants and plasma levels of one of these associated proteins, clusterin, have been identified as risk factors for AD. Read More

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Purification of MBP fusion proteins using engineered DARPin affinity matrix.

Int J Biol Macromol 2021 Jul 21;187:105-112. Epub 2021 Jul 21.

Center for Interdisciplinary Biosciences, Technology and Innovation Park of P.J. Šafárik University, Jesenná 5, 041 54 Košice, Slovakia. Electronic address:

Maltose binding protein (MBP) has a long history as an expression tag with the ability to increase the solubility of fused proteins. A critical step for obtaining a sufficient amount of the MBP fusion protein is purification. Commercially available amylose matrix for the affinity purification of MBP fusion proteins has two main issues: (i) low (micromolar) affinity and (ii) the limited number of uses due to the cleavage of polysaccharide matrix by the amylases, present in the crude cell extract. Read More

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The two faces of cyanide: an environmental toxin and a potential novel mammalian gasotransmitter.

FEBS J 2021 Jul 23. Epub 2021 Jul 23.

Chair of Pharmacology, Section of Medicine, University of Fribourg, Switzerland.

Cyanide is traditionally viewed as a cytotoxic agent, with its primary mode of action being the inhibition of mitochondrial Complex IV (cytochrome c oxidase). However, recent studies demonstrate that the effect of cyanide on Complex IV in various mammalian cells is biphasic: in lower concentrations (nanomolar to low micromolar) cyanide stimulates Complex IV activity, increases ATP production and accelerates cell proliferation, while at higher concentrations (high micromolar to low millimolar) it produces the previously known ("classic") toxic effects. The first part of the article describes the cytotoxic actions of cyanide in the context of environmental toxicology, and highlights pathophysiological conditions (e. Read More

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NMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands.

J Med Chem 2021 Jul 22. Epub 2021 Jul 22.

Division of Biomedical Sciences, School of Medicine, University of California, Riverside, 900 University Avenue, Riverside, California 92521, United States.

In this paper, we applied an innovative nuclear magnetic resonance (NMR)-guided screening and ligand design approach, named focused high-throughput screening by NMR (fHTS by NMR), to derive potent, low-molecular-weight ligands capable of mimicking interactions elicited by ephrin ligands on the receptor tyrosine kinase EphA4. The agents bind with nanomolar affinity, trigger receptor activation in cellular assays with motor neurons, and provide remarkable motor neuron protection from amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Structural studies on the complex between EphA4 ligand-binding domain and a most active agent provide insights into the mechanism of the agents at a molecular level. Read More

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Characterization of a functional V vasopressin receptor in the male rat kidney, evidence for crosstalk between V and V receptor signaling pathways.

Am J Physiol Renal Physiol 2021 07 20. Epub 2021 Jul 20.

Institut de génomique fonctionnelle, University of Montpellier, Montpellier, France.

Although vasopressin V receptor (V-R) mRNA was detected in the kidney, the precise renal localization, pharmacological and physiological properties of this receptor remain unknown. Using the selective V agonist d[Leu, Lys]VP, either fluorescent or radioactive, we showed that V-R is mainly present in principal cells of the inner medullary collecting duct (IMCD) in the male rat kidney. Protein and mRNA expression of V-R were very low compared to V receptor (V-R). Read More

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Potent Anticancer Effects of Epidithiodiketopiperazine NT1721 in Cutaneous T Cell Lymphoma.

Cancers (Basel) 2021 Jul 5;13(13). Epub 2021 Jul 5.

Department of Molecular Medicine, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of debilitating, incurable malignancies. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes, accounting for ~65% of CTCL cases. Patients with advanced disease have a poor prognosis and low median survival rates of four years. Read More

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Epidermal Growth Factor Based Targeted Toxin for the Treatment of Bladder Cancer.

Anticancer Res 2021 Aug;41(8):3741-3746

Faculty of Medicine, University of Freiburg, Freiburg, Germany

Background/aim: Reports on over-expression of the epidermal growth factor receptor (EGFR) in bladder cancer and its function in tumorigenesis have suggested to target this antigen.

Materials And Methods: We generated the targeted toxin EGF-PE40 consisting of the human epidermal growth factor (EGF) as the binding domain and PE40, a truncated version of Pseudomonas Exotoxin A, as the toxin domain. EGF-PE40 was tested on EGFR-expressing bladder cancer cells in view of binding via flow cytometry, and cytotoxicity via WST viability assay. Read More

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Histone deacetylase inhibitor panobinostat induces antitumor activity in epithelioid sarcoma and rhabdoid tumor by growth factor receptor modulation.

BMC Cancer 2021 Jul 20;21(1):833. Epub 2021 Jul 20.

Gustave Roussy Cancer Center, INSERM U1015, Université Paris-Saclay, Villejuif, France.

Background: Epithelioid sarcomas and rhabdoid tumors are rare, aggressive malignancies with poor prognosis. Both are characterized by INI1 alterations and deregulation of growth factor receptors albeit their interaction has not been elucidated.

Methods: In this study, we investigated the activity of a panel of epigenetic modulators and receptor tyrosine kinase inhibitors in vitro on respective cell lines as well as on primary patient-derived epithelioid sarcoma cells, and in vivo on xenografted mice. Read More

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Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition by nanobodies.

PLoS One 2021 16;16(7):e0253364. Epub 2021 Jul 16.

MRC Protein Phosphorylation and Ubiquitylation Unit, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.

Of the 16 non-structural proteins (Nsps) encoded by SARS CoV-2, Nsp3 is the largest and plays important roles in the viral life cycle. Being a large, multidomain, transmembrane protein, Nsp3 has been the most challenging Nsp to characterize. Encoded within Nsp3 is the papain-like protease domain (PLpro) that cleaves not only the viral polypeptide but also K48-linked polyubiquitin and the ubiquitin-like modifier, ISG15, from host cell proteins. Read More

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Diarylethene-based photoswitchable inhibitors of serine proteases.

Angew Chem Int Ed Engl 2021 Jul 16. Epub 2021 Jul 16.

Karlsruhe Institute of Technology: Karlsruher Institut fur Technologie, Institute of Organic Chemistry, Fritz-Haber-Weg 6, 76131, Karlsruhe, GERMANY.

A bicyclic peptide scaffold was chemically adapted to generate diarylethene-based photoswitchable inhibitors of serine protease Bos taurus trypsin 1 (T1). Starting from a prototype molecule - sunflower trypsin inhibitor-1 ( SFTI-1 ) - we obtained light-controllable inhibitors of T1 with K i in the low nanomolar range, whose activity could be modulated over 20-fold by irradiation. The inhibitory potency as well as resistance to proteolytic degradation were systematically studied on a series of 17 SFTI-1 analogues. Read More

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Mapping the binding site topology of amyloid protein aggregates using multivalent ligands.

Chem Sci 2021 Jul 7;12(25):8892-8899. Epub 2021 Jun 7.

Department of Chemistry, University of Cambridge Lensfield Road Cambridge CB2 1EW UK

A key process in the development of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases is the aggregation of proteins to produce fibrillary aggregates with a cross β-sheet structure, amyloid. The development of reagents that can bind these aggregates with high affinity and selectivity has potential for early disease diagnosis. By linking two benzothiazole aniline (BTA) head groups with different length polyethylene glycol (PEG) spacers, fluorescent probes that bind amyloid fibrils with low nanomolar affinity have been obtained. Read More

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The assessment of Pseudomonas aeruginosa lectin LecA binding characteristics of divalent galactosides using multiple techniques.

Glycobiology 2021 Jul 10. Epub 2021 Jul 10.

Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.

Pseudomonas aeruginosa is a widespread opportunistic pathogen that is capable of colonizing various human tissues and is resistant to many antibiotics. LecA is a galactose binding tetrameric lectin involved in adhesion, infection and biofilm formation. This study reports on the binding characteristics of mono- and divalent (chelating) ligands to LecA using different techniques. Read More

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Guanidinoneomycin-maleimide molecular transporter: synthesis, chemistry and cellular uptake.

Org Biomol Chem 2021 Jul;19(29):6513-6520

Department of Chemistry, Material and Chemical Engineer "Giulio Natta", Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy.

Guanidinoglycosides are a class of non-cytotoxic molecular transporters capable of delivering high molecular weight bioactive cargos into cells at low nanomolar concentrations. Efficient bioconjugation with guanidinoglycosides has been previously demonstrated by utilizing a guanidinoneomycin decorated with a reactive but also unstable N-hydroxysuccinimmide ester-containing linker. Herein we report the synthesis, chemistry, and application of a new, stable guanidinoneomycin derivative armed with a highly specific maleimide moiety which allows for thiol-maleimide click chemistry, a highly popular bioconjugation strategy, widening the field of application of these intriguing and useful delivery vehicles. Read More

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Biochemical Barriers on the Path to Ocean Anoxia?

mBio 2021 Jul 13:e0133221. Epub 2021 Jul 13.

Department of Microbiology, Oregon State Universitygrid.4391.f, Corvallis, Oregon, USA.

The kinetics of microbial respiration suggests that, if excess organic matter is present, oxygen should fall to nanomolar levels in the range of the Michaelis-Menten constants (). Yet even in many biologically productive coastal regions, lowest observed O concentrations often remain several orders of magnitude higher than respiratory values. We propose the hypoxic barrier hypothesis (HBH) to explain this apparent discrepancy. Read More

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CTP promotes efficient ParB-dependent DNA condensation by facilitating one-dimensional diffusion from S.

Elife 2021 Jul 12;10. Epub 2021 Jul 12.

Department of Macromolecular Structures, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain.

Faithful segregation of bacterial chromosomes relies on the ParABS partitioning system and the SMC complex. In this work, we used single-molecule techniques to investigate the role of cytidine triphosphate (CTP) binding and hydrolysis in the critical interaction between centromere-like DNA sequences and the ParB CTPase. Using a combined optical tweezers confocal microscope, we observe the specific interaction of ParB with directly. Read More

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In quest of small-molecules as potent non-competitive inhibitors against influenza.

Bioorg Chem 2021 Jul 1;114:105139. Epub 2021 Jul 1.

Department of Pharmaceutical Chemistry, Prin K M Kundnani College of Pharmacy, Cuffe Parade, Mumbai 400005, India. Electronic address:

A series of scaffolds namely aurones, 3-indolinones, 4-quinolones and cinnamic acid-piperazine hybrids, was designed, synthesized and investigated in vitro against influenza A/H1N1pdm09 virus. Designed molecules adopted different binding mode i.e. Read More

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Aη-α and Aη-β peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo.

Alzheimers Res Ther 2021 Jul 8;13(1):125. Epub 2021 Jul 8.

Université Côte d'Azur, CNRS, IPMC, 660 Route des Lucioles, 06560, Valbonne, France.

Background: Amyloid precursor protein (APP) processing is central to Alzheimer's disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη-α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo. Read More

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Discovery of Cyclic Peptide Ligands to the SARS-CoV-2 Spike Protein Using mRNA Display.

ACS Cent Sci 2021 Jun 27;7(6):1001-1008. Epub 2021 May 27.

School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.

The COVID-19 pandemic, caused by SARS-CoV-2, has led to substantial morbidity, mortality, and disruption globally. Cellular entry of SARS-CoV-2 is mediated by the viral spike protein, and affinity ligands to this surface protein have the potential for applications as antivirals and diagnostic reagents. Here, we describe the affinity selection of cyclic peptide ligands to the SARS-CoV-2 spike protein receptor binding domain (RBD) from three distinct libraries (in excess of a trillion molecules each) by mRNA display. Read More

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Microaerobic Lifestyle at Nanomolar O Concentrations Mediated by Low-Affinity Terminal Oxidases in Abundant Soil Bacteria.

mSystems 2021 Jul 6:e0025021. Epub 2021 Jul 6.

Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria.

High-affinity terminal oxidases (TOs) are believed to permit microbial respiration at low oxygen (O) levels. Genes encoding such oxidases are widespread, and their existence in microbial genomes is taken as an indicator for microaerobic respiration. We combined respiratory kinetics determined via highly sensitive optical trace O sensors, genomics, and transcriptomics to test the hypothesis that high-affinity TOs are a prerequisite to respire micro- and nanooxic concentrations of O in environmentally relevant model soil organisms: acidobacteria. Read More

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Monoacylglycerol lipase (MAGL) inhibitors based on a diphenylsulfide-benzoylpiperidine scaffold.

Eur J Med Chem 2021 Jun 29;223:113679. Epub 2021 Jun 29.

Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy; Center for Instrument Sharing of the University of Pisa (CISUP), Lungarno Pacinotti 43, 56126, Pisa, Italy.

Monoacylglycerol lipase (MAGL) is an enzyme belonging to the endocannabinoid system that mainly metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG). Numerous studies have shown the involvement of this enzyme in various pathological conditions such as pain, cancer progression, Parkinson's and Alzheimer's disease, thus encouraging the development of new MAGL modulators. In this context, we developed new diphenylsulfide-benzoylpiperidine derivatives characterized by a high enzymatic MAGL inhibition activity in the low nanomolar range, a reversible mechanism of action and selectivity. Read More

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Cyanobiphenyls: Novel H receptor ligands with cholinesterase and MAO B inhibitory activity as multitarget compounds for potential treatment of Alzheimer's disease.

Bioorg Chem 2021 Jun 28;114:105129. Epub 2021 Jun 28.

Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland. Electronic address:

Alzheimer's disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no new molecules have shown successful results in clinical trials, thereby making the common "one compound - one target" paradigm questionable. Recently, the multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more effective in treating AD. Read More

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