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Showing 101 to 104 of 5186 entries
Published on January 10, 2023
Identifying Potential Molecular Targets in Fungi Based on (Dis)Similarities in Binding Site Architecture with Proteins of the Human Pharmacolome.
Abstract: Invasive fungal infections represent a public health problem that worsens over the years with the increasing resistance to current antimycotic agents. Therefore, there is a compelling medical need of widening the antifungal drug repertoire, following different methods such as drug repositioning, identification and validation of new molecular targets and developing new inhibitors against these targets. In this work we developed a structure-based strategy for drug repositioning and new drug design, which can be applied to infectious fungi and other pathogens. Instead of applying the commonly accepted off-target criterion to discard fungal proteins with close homologues in humans, the core of our approach consists in identifying fungal proteins with active sites that are structurally similar, but preferably not identical to binding sites of proteins from the so-called "human pharmacolome". Using structural information from thousands of human protein target-inhibitor complexes, we identified dozens of proteins in fungal species of the genera Histoplasma, Candida, Cryptococcus, Aspergillus and Fusarium, which might be exploited for drug repositioning and, more importantly, also for the design of new fungus-specific inhibitors. As a case study, we present the in vitro experiments performed with a set of selected inhibitors of the human mitogen-activated protein kinases 1/2 (MEK1/2), several of which showed a marked cytotoxic activity in different fungal species.
Published on January 10, 2023
Emerging TACnology: Heterobifunctional Small Molecule Inducers of Targeted Posttranslational Protein Modifications.
Abstract: Posttranslational modifications (PTMs) play an important role in cell signaling and they are often deregulated in disease. This review addresses recent advances in the development of heterobifunctional small molecules that enable targeting or hijacking PTMs. This emerging field is spearheaded by proteolysis-targeting chimeras (PROTACs), that induce ubiquitination of their targets and, thus, tag them for degradation by the proteasome. Within the last decade, several improvements have been made to enhance spatiotemporal control of PROTAC-induced degradation as well as cell permeability. Inspired by the success story of PROTACs, additional concepts based on chimeric small molecules have emerged such as phosphatase-recruiting chimeras (PhoRCs). Herein, an overview of strategies causing (de-)phosphorylation, deubiquitination as well as acetylation is provided, and the opportunities and challenges of heterobifunctional molecules for drug discovery are highlighted. Although significant progress has been achieved, a plethora of PTMs have not yet been covered and PTM-inducing chimeras will be helpful tools for chemical biology and could even find application in pharmacotherapy.
Published on January 7, 2023
Molecular docking, network pharmacology and experimental verification to explore the mechanism of Wulongzhiyangwan in the treatment of pruritus.
Abstract: Wulongzhiyangwan (WLZYW) is a Chinese prescription medicine for the treatment of pruritus, but its mechanism has not been clarified. The purpose of this study was to explore the mechanism of WLZYW in pruritus through network pharmacology analysis and experimental validation. The active components and corresponding targets of WLZYW were obtained from the Traditional Chinese Medicine Systematic Pharmacology (TCMSP) database. Pruritus-related targets were obtained from the GeneCards, TTD (Therapeutic Target Database), and DrugBank databases. The key compounds, core targets, main biological processes and signaling pathways related to WLZYW were identified by constructing and analyzing related networks. The binding affinity between WLZYW components and core targets was validated by AutoDock Vina software. In this study, RBL-2H3 cells were used to construct a degranulation model to simulate histamine-dependent pruritus. 10 chemical constituents, 235 targets and 3606 pruritus-related targets of WLZYW were obtained. Subsequently, 26 core targets were identified through analysis, VEGFA and AKT1 were the main candidates. A pathway enrichment analysis showed that overlapping targets were significantly enriched in the PI3K/AKT signaling pathway. A molecular docking analysis revealed tight binding of VEGF to three core compounds, kaempferol, luteolin and quercetin. Experiments showed that WZLYW inhibited mast cell degranulation, regulated VEGFa mRNA and protein expression levels by inhibiting PI3K/AKT and ERK1/2 signaling pathway activation. The mechanism of WZLYW in pruritus may be regulating VEGFa expression. Network pharmacology assays suggested that WLZYW downregulates VEGFa expression by regulating the PI3K/AKT and ERK1/2 signaling pathways in pruritis treatment.
Published on January 7, 2023
In Silico Investigation of the Human GTP Cyclohydrolase 1 Enzyme Reveals the Potential of Drug Repurposing Approaches towards the Discovery of Effective BH(4) Therapeutics.
Abstract: The GTP cyclohydrolase 1 enzyme (GTPCH1) is the rate-limiting enzyme of the tetrahydrobiopterin (BH(4)) biosynthetic pathway. Physiologically, BH(4) plays a crucial role as an essential cofactor for the production of catecholamine neurotransmitters, including epinephrine, norepinephrine and dopamine, as well as the gaseous signaling molecule, nitric oxide. Pathological levels of the cofactor have been reported in a number of disease states, such as inflammatory conditions, neuropathic pain and cancer. Targeting the GTPCH1 enzyme has great potential in the management of a number of disease pathologies associated with dysregulated BH(4) physiology. This study is an in silico investigation of the human GTPCH1 enzyme using virtual screening and molecular dynamic simulation to identify molecules that can be repurposed to therapeutically target the enzyme. A three-tier molecular docking protocol was employed in the virtual screening of a comprehensive library of over 7000 approved medications and nutraceuticals in order to identify hit compounds capable of binding to the GTPCH1 binding pocket with the highest affinity. Hit compounds were further verified by molecular dynamic simulation studies to provide a detailed insight regarding the stability and nature of the binding interaction. In this study, we identify a number of drugs and natural compounds with recognized anti-inflammatory, analgesic and cytotoxic effects, including the aminosalicylate olsalazine, the antiepileptic phenytoin catechol, and the phlorotannins phlorofucofuroeckol and eckol. Our results suggest that the therapeutic and clinical effects of hit compounds may be partially attributed to the inhibition of the GTPCH1 enzyme. Notably, this study offers an understanding of the off-target effects of a number of compounds and advocates the potential role of aminosalicylates in the regulation of BH(4) production in inflammatory disease states. It highlights an in silico drug repurposing approach to identify a potential means of safely targeting the BH(4) biosynthetic pathway using established therapeutic agents.
Published on January 6, 2023
Introducing the Bacterial and Viral Bioinformatics Resource Center (BV-BRC): a resource combining PATRIC, IRD and ViPR.
Abstract: The National Institute of Allergy and Infectious Diseases (NIAID) established the Bioinformatics Resource Center (BRC) program to assist researchers with analyzing the growing body of genome sequence and other omics-related data. In this report, we describe the merger of the PAThosystems Resource Integration Center (PATRIC), the Influenza Research Database (IRD) and the Virus Pathogen Database and Analysis Resource (ViPR) BRCs to form the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) https://www.bv-brc.org/. The combined BV-BRC leverages the functionality of the bacterial and viral resources to provide a unified data model, enhanced web-based visualization and analysis tools, bioinformatics services, and a powerful suite of command line tools that benefit the bacterial and viral research communities.
Published on January 6, 2023
ChemPert: mapping between chemical perturbation and transcriptional response for non-cancer cells.
Abstract: Prior knowledge of perturbation data can significantly assist in inferring the relationship between chemical perturbations and their specific transcriptional response. However, current databases mostly contain cancer cell lines, which are unsuitable for the aforementioned inference in non-cancer cells, such as cells related to non-cancer disease, immunology and aging. Here, we present ChemPert (https://chempert.uni.lu/), a database consisting of 82 270 transcriptional signatures in response to 2566 unique perturbagens (drugs, small molecules and protein ligands) across 167 non-cancer cell types, as well as the protein targets of 57 818 perturbagens. In addition, we develop a computational tool that leverages the non-cancer cell datasets, which enables more accurate predictions of perturbation responses and drugs in non-cancer cells compared to those based onto cancer databases. In particular, ChemPert correctly predicted drug effects for treating hepatitis and novel drugs for osteoarthritis. The ChemPert web interface is user-friendly and allows easy access of the entire datasets and the computational tool, providing valuable resources for both experimental researchers who wish to find datasets relevant to their research and computational researchers who need comprehensive non-cancer perturbation transcriptomics datasets for developing novel algorithms. Overall, ChemPert will facilitate future in silico compound screening for non-cancer cells.
Published on January 6, 2023
DrugCentral 2023 extends human clinical data and integrates veterinary drugs.
Abstract: DrugCentral monitors new drug approvals and standardizes drug information. The current update contains 285 drugs (131 for human use). New additions include: (i) the integration of veterinary drugs (154 for animal use only), (ii) the addition of 66 documented off-label uses and iii) the identification of adverse drug events from pharmacovigilance data for pediatric and geriatric patients. Additional enhancements include chemical substructure searching using SMILES and 'Target Cards' based on UniProt accession codes. Statistics of interests include the following: (i) 60% of the covered drugs are on-market drugs with expired patent and exclusivity coverage, 17% are off-market, and 23% are on-market drugs with active patents and exclusivity coverage; (ii) 59% of the drugs are oral, 33% are parenteral and 18% topical, at the level of the active ingredients; (iii) only 3% of all drugs are for animal use only; however, 61% of the veterinary drugs are also approved for human use; (iv) dogs, cats and horses are by far the most represented target species for veterinary drugs; (v) the physicochemical property profile of animal drugs is very similar to that of human drugs. Use cases include azaperone, the only sedative approved for swine, and ruxolitinib, a Janus kinase inhibitor.
Published on January 6, 2023
MiMeDB: the Human Microbial Metabolome Database.
Abstract: The Human Microbial Metabolome Database (MiMeDB) (https://mimedb.org) is a comprehensive, multi-omic, microbiome resource that connects: (i) microbes to microbial genomes; (ii) microbial genomes to microbial metabolites; (iii) microbial metabolites to the human exposome and (iv) all of these 'omes' to human health. MiMeDB was established to consolidate the growing body of data connecting the human microbiome and the chemicals it produces to both health and disease. MiMeDB contains detailed taxonomic, microbiological and body-site location data on most known human microbes (bacteria and fungi). This microbial data is linked to extensive genomic and proteomic sequence data that is closely coupled to colourful interactive chromosomal maps. The database also houses detailed information about all the known metabolites generated by these microbes, their structural, chemical and spectral properties, the reactions and enzymes responsible for these metabolites and the primary exposome sources (food, drug, cosmetic, pollutant, etc.) that ultimately lead to the observed microbial metabolites in humans. Additional, extensively referenced data about the known or presumptive health effects, measured biosample concentrations and human protein targets for these compounds is provided. All of this information is housed in richly annotated, highly interactive, visually pleasing database that has been designed to be easy to search, easy to browse and easy to navigate. Currently MiMeDB contains data on 626 health effects or bioactivities, 1904 microbes, 3112 references, 22 054 reactions, 24 254 metabolites or exposure chemicals, 648 861 MS and NMR spectra, 6.4 million genes and 7.6 billion DNA bases. We believe that MiMeDB represents the kind of integrated, multi-omic or systems biology database that is needed to enable comprehensive multi-omic integration.
Published on January 6, 2023
ChemFOnt: the chemical functional ontology resource.
Abstract: The Chemical Functional Ontology (ChemFOnt), located at https://www.chemfont.ca, is a hierarchical, OWL-compatible ontology describing the functions and actions of >341 000 biologically important chemicals. These include primary metabolites, secondary metabolites, natural products, food chemicals, synthetic food additives, drugs, herbicides, pesticides and environmental chemicals. ChemFOnt is a FAIR-compliant resource intended to bring the same rigor, standardization and formal structure to the terms and terminology used in biochemistry, food chemistry and environmental chemistry as the gene ontology (GO) has brought to molecular biology. ChemFOnt is available as both a freely accessible, web-enabled database and a downloadable Web Ontology Language (OWL) file. Users may download and deploy ChemFOnt within their own chemical databases or integrate ChemFOnt into their own analytical software to generate machine readable relationships that can be used to make new inferences, enrich their omics data sets or make new, non-obvious connections between chemicals and their direct or indirect effects. The web version of the ChemFOnt database has been designed to be easy to search, browse and navigate. Currently ChemFOnt contains data on 341 627 chemicals, including 515 332 terms or definitions. The functional hierarchy for ChemFOnt consists of four functional 'aspects', 12 functional super-categories and a total of 173 705 functional terms. In addition, each of the chemicals are classified into 4825 structure-based chemical classes. ChemFOnt currently contains 3.9 million protein-chemical relationships and approximately 10.3 million chemical-functional relationships. The long-term goal for ChemFOnt is for it to be adopted by databases and software tools used by the general chemistry community as well as the metabolomics, exposomics, metagenomics, genomics and proteomics communities.
Published on January 6, 2023
qPTM: an updated database for PTM dynamics in human, mouse, rat and yeast.
Abstract: Post-translational modifications (PTMs) are critical molecular mechanisms that regulate protein functions temporally and spatially in various organisms. Since most PTMs are dynamically regulated, quantifying PTM events under different states is crucial for understanding biological processes and diseases. With the rapid development of high-throughput proteomics technologies, massive quantitative PTM proteome datasets have been generated. Thus, a comprehensive one-stop data resource for surfing big data will benefit the community. Here, we updated our previous phosphorylation dynamics database qPhos to the qPTM (http://qptm.omicsbio.info). In qPTM, 11 482 553 quantification events among six types of PTMs, including phosphorylation, acetylation, glycosylation, methylation, SUMOylation and ubiquitylation in four different organisms were collected and integrated, and the matched proteome datasets were included if available. The raw mass spectrometry based false discovery rate control and the recurrences of identifications among datasets were integrated into a scoring system to assess the reliability of the PTM sites. Browse and search functions were improved to facilitate users in swiftly and accurately acquiring specific information. The results page was revised with more abundant annotations, and time-course dynamics data were visualized in trend lines. We expected the qPTM database to be a much more powerful and comprehensive data repository for the PTM research community.
Showing 101 to 104 of 5186 entries