The 17th World Congress of Basic and Clinical Pharmacology (WCP2014) is now rapidly approaching and several NC-IUPHAR members will be attending the Congress. The followings talks will be presented on Tuesday 15th July 2014 15.30-17.00 in Track 6 of the programme: NC-IUPHAR and the IUPHAR/BPS Guide to PHARMACOLOGY.

From Sir Colin Dollery, Clinical Translational Pharmacology group:

NC-IUPHAR 1987-2014 and beyond

At the Sydney, Australia IUPHAR Congress in 1987, when I became President of IUPHAR, the Executive Committee decided to establish NC-IUPHAR, a committee on receptor nomenclature. At this time there was very little structural knowledge of receptors but a standardised nomenclature system was badly needed. The rapid ascent of NC-IUPHAR owed much to its first chair, Paul Vanhoutte’s energy, persuasive talents, and infectious enthusiasm. It was clear that a critical convergence was taking place between experimental and molecular pharmacology with a need to standardise nomenclature and provide an authoritative review of the evidence published on the properties of these molecules and the substances that interacted with them. A critical decision was to form over 60 expert committees with world wide membership to ensure a high quality of review. Since then there has been an exponential growth in activity, following the sequencing of the whole genome. Successive chairs, Bob Ruffolo and Michael Spedding, have contributing greatly to sustaining the quality and momentum of NC-IUPHAR as have those who have maintained the database. The volume and complexity of the data available continues to expand and the scope of the NC-IUPHAR-DB has expanded with it. Initially focused on GPCRs it has expanded to include ion channels, nuclear receptors, homo and heterodimers and current work on the kinome. NC-IUPHAR has an h-index of >60 and has a freely available database on receptors which will be described fully in this symposium. As the volume of BIG Data explodes the need for critical curation to maintain high standards of accuracy in documentation of targets and ligands in pharmacology and clinical pharmacology will grow too.

From Michael Spedding, NC-IUPHAR chairperson:

How two decades of NC-IUPHAR have helped resolve controversy in drug discovery

NC-IUPHAR (the nomenclature committee of IUPHAR) is engaged in a major task: How can we define all the main receptor and drug targets coded by the human genome, and put them in a database (guidetopharmacology.org) freely accessible to all? Even more important, link them to therapeutics and pharmacological target validation? The immense recent growth of knowledge about drug targets, with their crystal structures, has been a huge help to drug discovery and while IUPHAR classifications are regularly used, we are able to be proactive including targets, and contacting experts. We have 80 subcomittees of >700 pharmacologists contributing in their relevant fields, organised by our 5 curators, who are financed by the IUPHAR, the Wellcome trust, the BPS and our industrial sponsors. We have 2500 proteins in the database, with >6000 ligands, ~600 approved drugs. With the vast increase in knowledge, why is drug discovery not more successful? Perhaps because the increase in knowledge has been matched by the increase in variables affecting drug-receptor interactions. This is why we try and include data on how the new ‘knowledge frontiers’ of alternative spicing, non-coding RNAs, epigenetics, allostery, and biased signalling may affect drug discovery and development. An example : Doriano Fabbro, with Elena Faccenda as curator, has produced a complete database of kinases – with their pharmacology, thanks also to Novartis, Discoverx, Millipore and Reaction Biology providing data. This is an expert-based system, based on validated data, freely available to all, in our publications or on http://www.guidetopharmacology.org. However, these variables also lead to controversy and disagreement, sometimes fierce, between experts. NC-IUPHAR is the arbiter, and sometimes the target, of occasionally vivid controversy. Some examples will be given! But this means that we are relevant. NC-IUPHAR is open to all pharmacologists!

From Adam Pawson, Senior Database Curator:

IUPHAR-DB, GRAC and the IUPHAR/BPS Guide to PHARMACOLOGY

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 two well-established resources: (1) the IUPHAR Database [IUPHAR-DB; the original database of the IUPHAR Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) and driving force behind the development of the Guide to PHARMACOLOGY] and; (2) 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. GRAC has now been superseded by ‘The Concise Guide to PHARMACOLOGY’, a biennial snapshot of the overviews of the key properties of each target family, intended to be a quick desktop reference guide.

From Chris Southan,  Database Curator and Chairperson of the NC-IUPHAR Drugs and Targets Annotation Subcommittee

Analysing the drug targets in the human genome

Discerning the molecular mechanisms of action (mmoa) for drugs treating human diseases is crucially important. This talk will provide an overview of target numbers in IUPHAR/BPS Guide to PHARMACOLOGY, compare these to other sources and consider the wider implications for drug discovery. We have developed stringent mapping criteria for primary targets (i.e. identifying those direct protein interactions mechanistically causative for therapeutic efficacy). This includes inter-source corroboration by intersecting multiple drug sources inside PubChem to produce consensus structure sets. The analogous approach is used to intersect published target lists and database subsets at the UniProtKB/Swiss-Prot identity level. Our cumulative curation results reveal that structure representation differences, data provenance and variability of assay results, are major issues for experimental pharmacology and global database quality. While our activity mappings encompass some polypharmacology (e.g. dual inhibitors and kinase panel screens) our strategic choice is to annotate minimal rather than maximal target sets. The consequent increased precision gives our database high utility for data mining, linking and cross-referencing. Our small-molecule figures are currently converging to ~200 human protein primary targets for ~1000 consensus chemical structures of approved drugs. Target lists from other sources are typically larger and show a degree of discordance. Comparative analysis of these lists by their UniProt ID content and Gene Ontology distributions suggests differences in curatorial selection are the main cause of divergence. The global target landscape thus shows paradoxical trends. On the one hand, cumulative drug research output and recent expansions (e.g. epigenetic targets and orphan diseases) have pushed bioactive compounds from papers or patents to above 2 million and chemically modulatable human proteins above 1500 (PMID:24204758). On the other hand, reports of Phase II clinical efficacy failure, with implicit target de-validation, are frequent. In addition, our assessment of drug approval data from 2009 to 2013 indicates new targets (i.e. first-in-class mmoas) are so low as to threaten the sustainability of the pharmaceutical industry. Causes and consequences of these paradoxes, along with utilities for minimal and maximal druggable genomes, will be discussed.

From Simon Maxwell, Educational Site Project Leader

The IUPHAR/ASPET Pharmacology Education Project

Pharmacology has been the science at the heart of many of the advances in healthcare that we now take for granted. Those advances have depended on expertise in all areas from basic pharmacology through translational research to prescribing and monitoring the use of medicines by patients. Each step has required individuals with a clear grasp of the fundamental principles of pharmacology and clinical pharmacology supported by knowledge of the actions of specific drugs. For many scientists, and in many academic institutions, there has been an erosion of the visibility and profile of the pharmacological sciences as we move progressively into an era of inter-disciplinarity. The IUPHAR/ASPET Pharmacology Education Project seeks to bridge this gap and promote learning in pharmacology to a worldwide audience. The specific aims of the project are to: (i) produce a simple, attractive easily searchable resource that will support students of the pharmacological and other biomedical sciences, as well as health professions students including medicine, nursing, pharmacy and others; (ii) make high quality resources available to support pharmacology educators; and (iii) service the needs of students and teachers in resource-poor countries or where pharmacology is less well developed. The project has been supported for the first two years by a generous grant from ASPET and will be led by an international Editorial Board bringing together individuals with demonstrable commitment to pharmacology education. That group will welcome the input of colleagues from around the world as it brings together links to existing resources and gradually creates new ones. The content will be divided broadly into four sections: pharmacology, clinical pharmacology, drugs and therapeutics. Each section will be divided into modules, which will have associated topics to which learning resources will be attached (e.g. web-links, articles, video and audio files, PowerPoint). The longer-term aspiration would be that each topic would have an associated summary text generated by the editors. In addition to this simple structure there might be additional content including a formulary, glossary, and discussion board.

Additionally, Chris will be presenting a poster entitled ‘Will the real drugs please stand up? with the following abstract:

BACKGROUND: A comparison of database subsets of approved drugs in 2009 recorded only 807 exact structures in-common (PMID:20298516).  Factors contributing to low overlap included semantic naming inconsistencies, ambiguity in structure representation and the fact that neither regulatory bodies nor pharmaceutical companies directly verify public electronic chemical database records.  This work is a current comparison of drug sources inside PubChem.

METHODS: We selected submitters that nominally included small-molecule drug collections and International Non-proprietary names (INNs) and/or US approved names (USANS).  Unions, intersects and differences were derived by using the Entrez query history interface to perform Boolean operations on retrieved sets. Additional filters were explored, including salt-stripping by selecting a covalent unit count of 1.

RESULTS: DrugBank 3.0 declares 1,541 small-molecule drugs and the term “approved” returned 1,424 substances (SIDs) in PubChem. These collapse to 1,392 compounds (CIDs), and removal of mixtures reduces to 1,325.  The Therapeutic Target Database (TTD) declares 1,540 approved drugs on their website. The CID overlap with the DrugBank 1,325 was 1,108, and the equivalent figure for ChEMBL_17 was 1,141. The three-way consensus (from the DrugBank starting point) was 1,003.  The term INN retrieves 7,916 CIDS, reducing to 7,180 single-components. USAN brings back 5,494 of which only 3,204 are single-component (i.e. more salt forms are designated as USANs). Of the 1,108 3-way set, 927 have an INN or USAN. The “same connectivity” query indicates, on average, each of the 927 have nearly 20 canonically-related CIDs. Issues associated with these metrics will be outlined and, depending on new source releases, the numbers will be updated.

CONCLUSIONS: A surprising degree of non-overlap persists in drug structures. Our results are not a criticism of the valuable sources but further analysis is needed of the multiplicity of structural representations and fuzzy naming of essentially the same canonical drugs inside PubChem. This important issue in cheminformatics extends beyond the INNs to all pharmacologically active structures. It also rationalises our IUPHAR/BPS Guide to PHARMACOLOGY strategic choice of focusing on consensus sets for curation. This work indicates definitive drug lists will remain elusive until there is more collective engagement for provenance, standardisation and cross-mapping.

This poster (no.529) will be displayed on Monday 14th and Tuesday 15th July but is also available to view on SlideShare.

In April one of our curators, Helen Benson, represented the team at the Seventh International Biocuration Conference at the University of Toronto, and presented a poster outlining our approved drug and clinical target curation. This visit followed the previous year’s meeting of the International Society for Biocuration in Cambridge, UK, attended by both Helen and database developer Joanna Sharman.

Over the 4 days of the conference, the programme of talks and workshops covered many themes relevant to our work, as well as discussing the challenges facing biocurators today. These challenges include how curatorial work will evolve in an age of big data, and the role of crowdsourcing and text mining in managing the volume of biological data to be included in online databases. Keynote speakers Suzanna Lewis and Lincoln Stein discussed these themes with their respective talks on optimisation of curation and whether Big Data will crush curation.

One of the main themes from the talks and the workshops was the role and implementation of clinical and anatomical ontologies to databases. Additionally, several talks discussed data standards and controlled vocabularies, with particular regard to pathway curation. This issue is particularly pertinent to us as we now include enzyme pathways in our database.

Our team of curators has now expanded to 4, and our pipeline for ligand and target curation is constantly evolving to achieve optimum methods. It was therefore invaluable for us to learn more about the projects of other research groups, and to hear about which areas have become key focus points for the field. As always, it was a pleasure to meet others working in the field and we look forward to attending this event in the future.

Our database developer, Joanna Sharman, attended Edinburgh Neuroscience Day, an annual day of talks and poster presentations involving over 300 researchers with an interest in neuroscience.

Joanna also attended and presented a poster at the Barcelona GPCR Spring Conference organised by the GLISTEN network. This included presenting and discussing proposals for collaborations at the GPCRDB Satellite Meeting.

Joanna was also invited to attend a workshop on Computational Challenges in Data Citation at the University of Pennsylvania, Philadelphia, which brought together three groups of people (Computer Scientists, Information Scientists and Data Scientists) to explore the technical challenges and research opportunities posed by the increasing demand to generate citations for large, complex datasets.

Chemical curator Chris Southan started his 2014 representations with an invited visit to the April 29th – May 1st BioIT World, Boston, as co-organiser and presenter at a Workshop entitled “A Bar Code for Chemical Structures:Using the InChI to Transform Connectivity between Chemistry, Biology, Biomedicine and Drug Discovery”.

His individual workshop presentation was entitled “Transformative Utility of InChIKey Searching in the Mother of all Databases”.

A poster related to the database was also presented on “Will the real drugs please stand up?”.

In May 6th Chris had the privilege of being one of the opponents in a (successful) PhD examination for The Faculty of Pharmaceutical Sciences, University of Copenhagen. The trip included a presentation to the department and the GPCRDB team entitled “Will the real drugs and targets please stand up ? Evolving consensus-based curatorial strategies”.

On June 1-5th Chris attended the 10th International Conference on Chemical Structures. His oral presentation was entitled “Will the real drug targets please stand up?”.

As an alumnus from his work on the ELIXIR project in 2008/9 Chris attended the June 12th EMBL-EBI 20th Anniversary celebrations. He also took the opportunity to visit the EBI and Cambridge on the next day for discussions with a range of collaborators including UniProt, MEROPS, ChEMBL and NextMove Software.

Database Principal Investigator Jamie Davies attended the SULSA Synthetic Biology Meeting, in Edinburgh on 10th June and presented our poster “Exploiting Edinburgh’s Guide to PHARMACOLOGY database as a source of protein design information for synthetic biology”.

We recommend that all our users consider attending WCP2014 (early bird registration has now been extended until March 31st). Members of the IUPHAR/BPS Guide to PHARMACOLOGY database team, and NC-IUPHAR committee members will be attending and look forward to meeting you there. A number of presentations by NC-IUPHAR committee and subcommittee members are scheduled, outlined below:

Plenary lectures

• Arthur Christopoulos-IUPHAR Analytical Pharmacology lecture- Adventures in Allostery: From structure to function
• Yoshikatsu Kanai – Amino acid transporters in oncology
• Simon Maxwell – Challenges in training tomorrow’s prescribers
• Kozo Kaibuchi – Protein Phosphorylation in Signal transduction
• Richard Neubig – Signal transduction in therapeutics
• Doriano Fabbro – Tyrosine kinase inhibitors
• Martin Michel – Autonomic pharmacology of the urogenital tract

Symposia including NC-IUPHAR affiliates

• Orphan G protein-coupled receptors- What are the new ligand and new drug targets? (Anthony Davenport, Janet Maguire, Stephen Alexander, Adam Pawson)
• Structural Basis for Ion Channel Pharmacology (including Bill Catterall)
• NC-IUPHAR and the IUPHAR/BPS Guide to PHARMACOLOGY (Sir Colin Dollery, Michael Spedding, Simon Maxwell, Adam Pawson, Chris Southan)
• Update in geriatric pharmacology Optimal Prescribing in Older Patients: The challenge of Multiple Comorbid Conditions and Polypharmacy (including Darrell Abernethy)
• Evolution, sport and modern diseases (including Michael Spedding)
• Emerging Drug Targets (including Richard Neubig)
• Glucocorticoids: new insights into mechanisms of action (including John Cidlowski)
• Epigenetic mechanisms in cell- and drug-based heart failure therapies (including Lutz Hein)

Full details for the meeting and a detailed schedule can be found on the event website. Click on the following links for flyers outlining event speakers, focused target sessions and symposia and events in and around Cape Town.