The IUPHAR/BPS Guide to PHARMACOLOGY in 2024.

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb; https://www.guidetopharmacology.org) is an open-access, expert-curated, online database that provides succinct overviews and key references for pharmacological targets and their recommended experimental ligands. It includes over 3039 protein targets and 12 163 ligand molecules, including approved drugs, small molecules, peptides and antibodies. Here, we report recent developments to the resource and describe expansion in content over the six database releases made during the last two years. The database update section of this paper focuses on two areas relating to important global health challenges. The first, SARS-CoV-2 COVID-19, remains a major concern and we describe our efforts to expand the database to include a new family of coronavirus proteins. The second area is antimicrobial resistance, for which we have extended our coverage of antibacterials in partnership with AntibioticDB, a collaboration that has continued through support from GARDP. We discuss other areas of curation and also focus on our external links to resources such as PubChem that bring important synergies to the resources.

High-Throughput SARS-CoV-2 Antiviral Testing Method Using the Celigo Image Cytometer.

The COVID-19 pandemic has created a worldwide public health crisis that has since resulted in 6.8 million reported deaths. The pandemic prompted the immediate response of researchers around the world to engage in rapid vaccine development, surveillance programs, and antiviral testing, which resulted in the delivery of multiple vaccines and repurposed antiviral drug candidates. However, the emergence of new highly transmissible SARS-CoV-2 variants has renewed the desire for discovering new antiviral drug candidates with high efficacy against the emerging variants of concern. Traditional antiviral testing methods employ the plaque-reduction neutralization tests (PRNTs), plaque assays, or RT-PCR analysis, but each assay can be tedious and time-consuming, requiring 2-3 days to complete the initial antiviral assay in biologically relevant cells, and then 3-4 days to visualize and count plaques in Vero cells, or to complete cell extractions and PCR analysis. In recent years, plate-based image cytometers have demonstrated high-throughput vaccine screening methods, which can be adopted for screening potential antiviral drug candidates. In this work, we developed a high-throughput antiviral testing method employing the Celigo Image Cytometer to investigate the efficacy of antiviral drug candidates on SARS-CoV-2 infectivity using a fluorescent reporter virus and their safety by measuring the cytotoxicity effects on the healthy host cell line using fluorescent viability stains. Compared to traditional methods, the assays defined here eliminated on average 3-4 days from our standard processing time for antiviral testing. Moreover, we were able to utilize human cell lines directly that are not typically amenable to PRNT or plaque assays. The Celigo Image Cytometer can provide an efficient and robust method to rapidly identify potential antiviral drugs to effectively combat the rapidly spreading SARS-CoV-2 virus and its variants during the pandemic.

The IUPHAR/BPS guide to PHARMACOLOGY in 2022: curating pharmacology for COVID-19, malaria and antibacterials.

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb; www.guidetopharmacology.org) is an open-access, expert-curated database of molecular interactions between ligands and their targets. We describe expansion in content over nine database releases made during the last two years, which has focussed on three main areas of infection. The COVID-19 pandemic continues to have a major impact on health worldwide. GtoPdb has sought to support the wider research community to understand the pharmacology of emerging drug targets for SARS-CoV-2 as well as potential targets in the host to block viral entry and reduce the adverse effects of infection in patients with COVID-19. We describe how the database rapidly evolved to include a new family of Coronavirus proteins. Malaria remains a global threat to half the population of the world. Our database content continues to be enhanced through our collaboration with Medicines for Malaria Venture (MMV) on the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY (www.guidetomalariapharmacology.org). Antibiotic resistance is also a growing threat to global health. In response, we have extended our coverage of antibacterials in partnership with AntibioticDB.

Sphingolipids metabolism alteration in the central nervous system: Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.

Sphingolipids are complex lipids. They play a structural role in neurons, but are also involved in regulating cellular communication, and neuronal differentiation and maturation. There is increasing evidence to suggest that dysregulated metabolism of sphingolipids is linked to neurodegenerative processes in amyotrophic lateral sclerosis (ALS), Parkinson's disease and Gaucher's disease. In this review, we provide an overview of the role of sphingolipids in the development and maintenance of the nervous system. We describe the implications of altered metabolism of sphingolipids in the pathophysiology of certain neurodegenerative diseases, with a primary focus on ALS. Finally, we provide an update of potential treatments that could be used to target the metabolism of sphingolipids in neurodegenerative diseases.

Future directions for the discovery of natural product-derived immunomodulating drugs: an IUPHAR positional review.

Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least the novel targets that have emerged in recent times and the development of state-of-the-art technologies that can be applied to drug discovery from natural sources. Although progress has been made with some immunomodulating drugs, there remains a pressing need for new agents that can be used to treat the wide variety of conditions that arise from disruption, or over-activation, of the immune system; natural products may therefore be key in filling this gap. Recognising that, at present, there is no authoritative article that details the current state-of-the-art of the immunomodulatory activity of natural products, this in-depth review has arisen from a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) Natural Products and Immunopharmacology Sections, with contributions from a number of world-leading researchers in the field of natural product drug discovery, to provide a "position statement" on what natural products has to offer in the search for new immunomodulatory argents. To this end, we provide a historical look at previous discoveries of naturally occurring immunomodulators, present a picture of the current status of the field and provide insight into the future opportunities and challenges for the discovery of new drugs to treat immune-related diseases.

The IUPHAR/BPS Guide to PHARMACOLOGY in 2020: extending immunopharmacology content and introducing the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY.

The IUPHAR/BPS Guide to PHARMACOLOGY (www.guidetopharmacology.org) is an open-access, expert-curated database of molecular interactions between ligands and their targets. We describe significant updates made over the seven releases during the last two years. The database is notably enhanced through the continued linking of relevant pharmacology with key immunological data types as part of the IUPHAR Guide to IMMUNOPHARMACOLOGY (www.guidetoimmunopharmacology.org) and by a major new extension, the IUPHAR/MMV Guide to Malaria PHARMACOLOGY (www.guidetomalariapharmacology.org). The latter has been constructed in partnership with the Medicines for Malaria Venture, an organization dedicated to identifying, developing and delivering new antimalarial therapies that are both effective and affordable. This is in response to the global challenge of over 200 million cases of malaria and 400 000 deaths worldwide, with the majority in the WHO Africa Region. It provides new pharmacological content, including molecular targets in the malaria parasite, interaction data for ligands with antimalarial activity, and establishes curation of data from screening assays, used routinely in antimalarial drug discovery, against the whole organism. A dedicated portal has been developed to provide quick and focused access to these new data.

Guide to Immunopharmacology: a database to boost immunology education, research and therapy.

In the era of big data, the establishment of a free database, containing all the immune drug targets and associated cell types, is of great value. To this aim, the Guide to Immunopharmacology has been created in a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) and the International Union of Immunological Societies (IUIS). Here we highlight the structure and content of the database, which includes up-to-date quantitative information on the fundamental science underlying each immune target. A set of practical examples and tools for data mining are summarized to support immune research into drug discovery and therapeutics.

The IUPHAR Guide to Immunopharmacology: connecting immunology and pharmacology.

Given the critical role that the immune system plays in a multitude of diseases, having a clear understanding of the pharmacology of the immune system is crucial to new drug discovery and development. Here we describe the International Union of Basic and Clinical Pharmacology (IUPHAR) Guide to Immunopharmacology (GtoImmuPdb), which connects expert-curated pharmacology with key immunological concepts and aims to put pharmacological data into the hands of immunologists. In the pursuit of new therapeutics, pharmacological databases are a vital resource to researchers through providing accurate information on the fundamental science underlying drug action. This extension to the existing IUPHAR/British Pharmacological Society Guide to Pharmacology supports research into the development of drugs targeted at modulating immune, inflammatory or infectious components of disease. To provide a deeper context for how the resource can support research we show data in GtoImmuPdb relating to a case study on the targeting of vascular inflammation.

The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY.

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, www.guidetopharmacology.org) and its precursor IUPHAR-DB, have captured expert-curated interactions between targets and ligands from selected papers in pharmacology and drug discovery since 2003. This resource continues to be developed in conjunction with the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS). As previously described, our unique model of content selection and quality control is based on 96 target-class subcommittees comprising 512 scientists collaborating with in-house curators. This update describes content expansion, new features and interoperability improvements introduced in the 10 releases since August 2015. Our relationship matrix now describes ∼9000 ligands, ∼15 000 binding constants, ∼6000 papers and ∼1700 human proteins. As an important addition, we also introduce our newly funded project for the Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb, www.guidetoimmunopharmacology.org). This has been 'forked' from the well-established GtoPdb data model and expanded into new types of data related to the immune system and inflammatory processes. This includes new ligands, targets, pathways, cell types and diseases for which we are recruiting new IUPHAR expert committees. Designed as an immunopharmacological gateway, it also has an emphasis on potential therapeutic interventions.

The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands.

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, http://www.guidetopharmacology.org) provides expert-curated molecular interactions between successful and potential drugs and their targets in the human genome. Developed by the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS), this resource, and its earlier incarnation as IUPHAR-DB, is described in our 2014 publication. This update incorporates changes over the intervening seven database releases. The unique model of content capture is based on established and new target class subcommittees collaborating with in-house curators. Most information comes from journal articles, but we now also index kinase cross-screening panels. Targets are specified by UniProtKB IDs. Small molecules are defined by PubChem Compound Identifiers (CIDs); ligand capture also includes peptides and clinical antibodies. We have extended the capture of ligands and targets linked via published quantitative binding data (e.g. Ki, IC50 or Kd). The resulting pharmacological relationship network now defines a data-supported druggable genome encompassing 7% of human proteins. The database also provides an expanded substrate for the biennially published compendium, the Concise Guide to PHARMACOLOGY. This article covers content increase, entity analysis, revised curation strategies, new website features and expanded download options.

Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase.

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. Growing evidence suggests a link between changes in lipid metabolism and ALS. Here, we used UPLC/TOF-MS to survey the lipidome in SOD1(G86R) mice, a model of ALS. Significant changes in lipid expression were evident in spinal cord and skeletal muscle before overt neuropathology. In silico analysis also revealed appreciable changes in sphingolipids including ceramides and glucosylceramides (GlcCer). HPLC analysis showed increased amounts of GlcCer and downstream glycosphingolipids (GSLs) in SOD1(G86R) muscle compared with wild-type littermates. Glucosylceramide synthase (GCS), the enzyme responsible for GlcCer biosynthesis, was up-regulated in muscle of SOD1(G86R) mice and ALS patients, and in muscle of wild-type mice after surgically induced denervation. Conversely, inhibition of GCS in wild-type mice, following transient peripheral nerve injury, reversed the overexpression of genes in muscle involved in oxidative metabolism and delayed motor recovery. GCS inhibition in SOD1(G86R) mice also affected the expression of metabolic genes and induced a loss of muscle strength and morphological deterioration of the motor endplates. These findings suggest that GSLs may play a critical role in ALS muscle pathology and could lead to the identification of new therapeutic targets.

A new nomenclature for classifying psychotropic drugs.

The Neuroscience-based Nomenclature (NbN) for psychotropic drugs was developed as an alternative to the current Anatomical Therapeutic Chemical (ATC) indication-based classification in order to provide more precise designations for this drug class. The ATC nomenclature for psychotherapeutics is limited in that it fails to specify either pharmacological domains or mechanism of action and also does not describe all the potential uses of a particular agent. The disconnect between the drug classification and its clinical use is not very useful for scientific purposes and is confusing for patients and caregivers, often leading to a misunderstanding of the intended effects of the prescribed medication and, most importantly, to low treatment adherence. The NbN classifies psychopharmacological agents on the basis of contemporary scientific information on their pharmacology and mechanisms of action so as to provide physicians clear alternatives when selecting or altering therapeutic regimens. The classification of each psychotropic drug includes four additional dimensions: approved indications; efficacy and side effects; practical note; neurobiology. By emphasizing the pharmacology and the molecular mechanism of action, NbN provides a vehicle for clinicians and basic scientists to improve the understanding and clinical use of this important drug class.

International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands.

Allosteric interactions play vital roles in metabolic processes and signal transduction and, more recently, have become the focus of numerous pharmacological studies because of the potential for discovering more target-selective chemical probes and therapeutic agents. In addition to classic early studies on enzymes, there are now examples of small molecule allosteric modulators for all superfamilies of receptors encoded by the genome, including ligand- and voltage-gated ion channels, G protein-coupled receptors, nuclear hormone receptors, and receptor tyrosine kinases. As a consequence, a vast array of pharmacologic behaviors has been ascribed to allosteric ligands that can vary in a target-, ligand-, and cell-/tissue-dependent manner. The current article presents an overview of allostery as applied to receptor families and approaches for detecting and validating allosteric interactions and gives recommendations for the nomenclature of allosteric ligands and their properties.

The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands.

The International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to PHARMACOLOGY (http://www.guidetopharmacology.org) is a new open access resource providing pharmacological, chemical, genetic, functional and pathophysiological data on the targets of approved and experimental drugs. Created under the auspices of the IUPHAR and the BPS, the portal provides concise, peer-reviewed overviews of the key properties of a wide range of established and potential drug targets, with in-depth information for a subset of important targets. The resource is the result of curation and integration of data from the IUPHAR Database (IUPHAR-DB) and the published BPS 'Guide to Receptors and Channels' (GRAC) compendium. The data are derived from a global network of expert contributors, and the information is extensively linked to relevant databases, including ChEMBL, DrugBank, Ensembl, PubChem, UniProt and PubMed. Each of the ∼6000 small molecule and peptide ligands is annotated with manually curated 2D chemical structures or amino acid sequences, nomenclature and database links. Future expansion of the resource will complete the coverage of all the targets of currently approved drugs and future candidate targets, alongside educational resources to guide scientists and students in pharmacological principles and techniques.

International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands.

In 2005, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) published a catalog of all of the human gene sequences known or predicted to encode G protein-coupled receptors (GPCRs), excluding sensory receptors. This review updates the list of orphan GPCRs and describes the criteria used by NC-IUPHAR to recommend the pairing of an orphan receptor with its cognate ligand(s). The following recommendations are made for new receptor names based on 11 pairings for class A GPCRs: hydroxycarboxylic acid receptors [HCA1 (GPR81) with lactate, HCA2 (GPR109A) with 3-hydroxybutyric acid, HCA3 (GPR109B) with 3-hydroxyoctanoic acid]; lysophosphatidic acid receptors [LPA4 (GPR23), LPA5 (GPR92), LPA6 (P2Y5)]; free fatty acid receptors [FFA4 (GPR120) with omega-3 fatty acids]; chemerin receptor (CMKLR1; ChemR23) with chemerin; CXCR7 (CMKOR1) with chemokines CXCL12 (SDF-1) and CXCL11 (ITAC); succinate receptor (SUCNR1) with succinate; and oxoglutarate receptor [OXGR1 with 2-oxoglutarate]. Pairings are highlighted for an additional 30 receptors in class A where further input is needed from the scientific community to validate these findings. Fifty-seven human class A receptors (excluding pseudogenes) are still considered orphans; information has been provided where there is a significant phenotype in genetically modified animals. In class B, six pairings have been reported by a single publication, with 28 (excluding pseudogenes) still classified as orphans. Seven orphan receptors remain in class C, with one pairing described by a single paper. The objective is to stimulate research into confirming pairings of orphan receptors where there is currently limited information and to identify cognate ligands for the remaining GPCRs. Further information can be found on the IUPHAR Database website (http://www.iuphar-db.org).

Key challenges for the creation and maintenance of specialist protein resources.

As the volume of data relating to proteins increases, researchers rely more and more on the analysis of published data, thus increasing the importance of good access to these data that vary from the supplemental material of individual articles, all the way to major reference databases with professional staff and long-term funding. Specialist protein resources fill an important middle ground, providing interactive web interfaces to their databases for a focused topic or family of proteins, using specialized approaches that are not feasible in the major reference databases. Many are labors of love, run by a single lab with little or no dedicated funding and there are many challenges to building and maintaining them. This perspective arose from a meeting of several specialist protein resources and major reference databases held at the Wellcome Trust Genome Campus (Cambridge, UK) on August 11 and 12, 2014. During this meeting some common key challenges involved in creating and maintaining such resources were discussed, along with various approaches to address them. In laying out these challenges, we aim to inform users about how these issues impact our resources and illustrate ways in which our working together could enhance their accuracy, currency, and overall value.

IUPHAR-DB: updated database content and new features.

The International Union of Basic and Clinical Pharmacology (IUPHAR) database, IUPHAR-DB (http://www.iuphar-db.org) is an open access, online database providing detailed, expert-driven annotation of the primary literature on human and rodent receptors and other drug targets, together with the substances that act on them. The present release includes information on the products of 646 genes from four major protein classes (G protein-coupled receptors, nuclear hormone receptors, voltage- and ligand-gated ion channels) and ∼3180 bioactive molecules (endogenous ligands, licensed drugs and key pharmacological tools) that interact with them. We have described previously the classification and curation of data for small molecule ligands in the database; in this update we have annotated 366 endogenous peptide ligands with their amino acid sequences, post-translational modifications, links to precursor genes, species differences and relationships with other molecules in the database (e.g. those derived from the same precursor). We have also matched targets with their endogenous ligands (peptides and small molecules), with particular attention paid to identifying bioactive peptide ligands generated by post-translational modification of precursor proteins. Other improvements to the database include enhanced information on the clinical relevance of targets and ligands in the database, more extensive links to other databases and a pilot project for the curation of enzymes as drug targets.

IUPHAR-DB: new receptors and tools for easy searching and visualization of pharmacological data.

The IUPHAR database is an established online reference resource for several important classes of human drug targets and related proteins. As well as providing recommended nomenclature, the database integrates information on the chemical, genetic, functional and pathophysiological properties of receptors and ion channels, curated and peer-reviewed from the biomedical literature by a network of experts. The database now includes information on 616 gene products from four superfamilies in human and rodent model organisms: G protein-coupled receptors, voltage- and ligand-gated ion channels and, in a recent update, 49 nuclear hormone receptors (NHRs). New data types for NHRs include details on co-regulators, DNA binding motifs, target genes and 3D structures. Other recent developments include curation of the chemical structures of approximately 2000 ligand molecules, providing electronic descriptors, identifiers, link-outs and calculated molecular properties, all available via enhanced ligand pages. The interface now provides intelligent tools for the visualization and exploration of ligand structure-activity relationships and the structural diversity of compounds active at each target. The database is freely available at http://www.iuphar-db.org.