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

IUPHAR: from San Francisco to Beijing

I here reaffirm some of the points that I made in the manifesto for UK clinical pharmacology [1], in response to letters from others. Much of what I wrote in the manifesto addresses points that correspondents have made, but as some of the important points may not have been clear on a first reading, I shall reiterate them and add clarifications. I am surprised that Professor Page [2] should think that I have taken no cognizance of the erosion of the discipline of pharmacology in recent years. Nothing that I said, wrote or did, while I was President-Elect and President of the British Pharmacological Society (BPS) during 2006 to 2009, should have given that impression. If he doubts this, and my commitment to the integration of all pharmacological science across the clinical and non-clinical spectra, he may want to reread some of my articles in the newsletter of the BPS, previously called pA2, now called Pharmacology Matters[3, 4], and indeed the manifesto itself, where I wrote that ‘the importance of integrating pharmacology and clinical pharmacology cannot be overestimated’. In relation to this, I strongly believe that the distinction that many make between basic and applied science is a false dichotomy. As I wrote in the manifesto, ‘functions in biology emerge … as a result of integration of different components of relevant systems at different levels.’ This is true of pharmacology and clinical pharmacology. Although it is sometimes useful to refer separately to basic and applied science, it is the crosstalk between them, at all levels and from one level to another, that is important. I have recently had the opportunity to make these views known more widely, in my opening plenary lecture at WorldPharma 2010, the 16th World Congress of the International Union of Basic and Clinical Pharmacology (IUPHAR). The contents of that lecture have been posted on the BPS's website [5].

Most medicines are chemical substances that work by interacting with specific target proteins in the body. The International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS) have joined forces to develop the Guide to PHARMACOLOGY (www.guidetopharmacology.org), a portal to information on the targets of licensed drugs and other targets of current research interest, such as those linked to human disease. Over the next 3 years, with support from the Wellcome Trust, IUPHAR and BPS, the Guide to PHARMACOLOGY portal will be expanded to cover all the targets of current licensed drugs and those with potential to be targets of future therapeutics. Our goal is to provide scientists, doctors, allied professions and the general public with a ‘one-stop shop’ source of information on how drugs work, and to help researchers to design experiments using the appropriate reagents.

Basic & Clinical Pharmacology & ToxicologyVolume 111, Issue 6 p. 361-361 Letter from the EditorFree Access Letter from the Editor First published: 14 November 2012 https://doi.org/10.1111/bcpt.12030AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat The three organizations, the International Union of Basic and Clinical Pharmacology (IUPHAR), the Council for International Organizations of Medical Sciences (CIOMS) and the World Health Organization (WHO), have recently published a joint position paper 1 on clinical pharmacology in health care, teaching and research. It is an updated and edited version of a similar position paper 2 published in Basic & Clinical Pharmacology & Toxicology in July 2010 in connection with the 16th World Congress on Basic and Clinical Pharmacology in Copenhagen. The new position paper can be downloaded from the website of CIOMS: www.cioms.ch. The ambition is that the document will set the scene for the discipline in the first half of the 21st century in accordance with the concepts of an earlier WHO report published as long ago as in 1970 3. As the Editor-in-Chief of BCPT has been deeply involved in writing the position paper, it will not be reviewed here. The aim of this letter is simply to draw the attention of the readers of BCPT to its existence. References 1Abernethy D, Birkett D, Brøsen K, Cascorbi I, Gustafsson LL, Hoppu K et al. Clinical Pharmacology in health care, teaching and research. Edited by: M Orme, F Sjöqvist, D Birkett 2012. Available on www.cioms.ch 2Birkett D, Brøsen K, Cascorbi I, Gustafsson LL, Maxwell S, Rago L et al. Clinical pharmacology in research, teaching and health care: considerations by IUPHAR, the International Union of Basic and Clinical Pharmacology. Basic Clin Pharmacol Toxicol 2010; 107: 531– 59. 3 World Health Organization, Clinical pharmacology. Scope, organization, training. Report of a WHO study group. World Health Organ Tech Rep Ser 1970; 446: 5– 21. Volume111, Issue6December 2012Pages 361-361 ReferencesRelatedInformation

A fundamental mistake in receptor theory has led to an enduring misunderstanding of how to estimate the affinity and efficacy of an agonist. These properties are inextricably linked and cannot be easily separated in any case where the binding of a ligand induces a conformation change in its receptor. Consequently, binding curves and concentration–response relationships for receptor agonists have no straightforward interpretation. This problem—the affinity–efficacy problem—remains overlooked and misunderstood despite it being recognized in 1987. To avoid the further propagation of this misunderstanding, we propose in this review that the affinity–efficacy problem should be included in the core curricula for pharmacology undergraduates proposed by the British Pharmacological Society and the International Union of Basic and Clinical Pharmacology (IUPHAR).

Development of a pharmaceutical database as an aid to the nonclinical detection of drug-induced cardiac toxicity

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb) is an open, expert-driven database of pharmacological targets and the substances that act on them. It is a joint initiative between the British Pharmacological Society (BPS) and the International Union of Basic and Clinical Pharmacology (IUPHAR), which aims to cover the human targets of licensed drugs and other likely targets of future therapeutics. This poster give an update on the recent activities of GtoPdb, including details of our coronavirus pharmacology information page.

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 European Association for Clinical Pharmacology and Therapeutics and the Journal <i>Basic &amp; Clinical Pharmacology &amp; Toxicology</i>

British Journal of Pharmacology (2007) 150, 129. doi:10.1038/sj.bjp.0707112

The International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee aims to improve the use of drugs in older adults and develop new therapeutic approaches for the syndromes and diseases of old age through advocacy, education, and research. In the present paper, we propose strategies relevant to drug development and evaluation, spanning preclinical and the full range of clinical studies. Drugs for older adults need to consider not only age, but also other characteristics common in geriatric patients, such as multimorbidity, polypharmacy, falls, cognitive impairment, and frailty. The IUPHAR Geriatric Committee's position statement on 'Measurement of Frailty in Drug Development and Evaluation' is included, highlighting 12 key principles that cover the spectrum of translational research. We propose that where older adults are likely to be major users of a drug, that frailty is measured at baseline and as an outcome. Preclinical models that replicate the age, frailty, duration of exposure, comorbidities, and co-medications of the proposed patients may improve translation. We highlight the potential application of recent technologies, such as physiologically based pharmacokinetic-pharmacodynamic modeling informed by frailty biology, and Artificial Intelligence, to inform personalized medicine for older patients. Considerations for the rapidly aging populations in low- and middle-income countries related to health-care and clinical trials are outlined. Involving older adults, their caregivers and health-care providers in all phases of research should improve drug development, evaluation, and outcomes for older adults internationally.

SummaryGiven 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 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.

Forty-two years ago the World Health Organization published a report that attempted to define the discipline of clinical pharmacology [1]. Since then, the scope of the discipline has expanded immeasurably. The number of available medicines has markedly increased, biological therapies are now having a profound impact on contemporary therapeutics and the range of conditions that can now be effectively managed by modern drug therapy is far greater than hitherto. Moreover, the impact of personalized medicine and pharmacogenetics is likely to change, fundamentally, the face of therapeutics in the future. But there are other issues, too, about which clinical pharmacologists now have to be concerned. The high acquisition cost of some new pharmaceutical products, coupled with resource constraints on global health care budgets, renders issues about their cost effectiveness becoming as relevant in developed countries as they are in developing ones. And those hoary old chestnuts of quality and safety, as well as striking an appropriate balance between benefit and risk, remain. It was therefore timely for the 1970 WHO report to be revised to take account of all these developments and Folke Sjoqvist, Michael Orme and Don Birkett have been masterminding its revision, now published as Clinical Pharmacology in Health Care, Teaching and Research [2], for several years. Together with an international group of contributors, they have overseen the preparation of a document that has been endorsed by WHO as well as by the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Council for International Organizations of Medical Sciences (CIOMS). This new report covers all the emergent, and emerging, issues. Some clinical pharmacologists might criticize it for failing to give sufficient attention to health technology assessment, health economics or pharmacoepidemiology. While I have inherent sympathies with these reservations, all these topics are discussed albeit briefly and, as a contributor to the report, I have to accept that to have gone into greater detail would have expanded the report to an extent that would have seriously diminished its impact. The report also includes two important appendices. One is a ‘model’ undergraduate core curriculum in clinical pharmacology, therapeutics and prescribing for medical students. The other is a ‘model’ curriculum for medical specialization in clinical pharmacology. Both will, I am sure, become global training standards. The report also recognizes, at least obliquely, the distinction between clinical pharmacology as a trade and as a discipline. The discipline of clinical pharmacology is far broader than the unique contributions that specialist clinical pharmacologists can themselves make. And here is the rub that has bedevilled our subject for two decades or more. The scope of clinical pharmacology is too broad for any of us to accomplish the totality with any degree of comfort. Or, as stated in the report, ‘… the list of ingredients in a contemporary clinical pharmacologist's work provides a menu too full for a single individual’. Necessarily, physicians trained in disciplines such as paediatrics, geriatrics, oncology and psychiatry carry out much important clinical pharmacological research and practice. Moreover, clinical pharmacology is undertaken by a new generation of prescribers in nursing and pharmacy. Significant research in clinical pharmacology is also performed by epidemiologists as well as by non-clinical personnel working in the pharmaceutical industry. The report recognizes, indeed welcomes, the diversity of disciplines involved in the practice of clinical pharmacology both as prescribers and as investigators. It emphasizes the important contributions that individual specialists, in other disciplines, make to clinical pharmacology, but at the same time defining, more clearly than hitherto, the special contributions of clinical pharmacologists themselves for the well-being of patients and the public. For this, especially, Folke Sjoqvist, Michael Orme and Don Birkett deserve our enduring gratitude.

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B).