The first GtoPdb and GtoImmuPdb beta release of 2018 includes plenty of target and ligand updates as well as announcing some important new features.
As always, full content statistics for release 2018.1 can be found on the database about page
New website features
Disease listing and disease pages
For the first time, disease information has been gathered together in one place, under a new menu bar option called “Diseases”, which links to a full listing of all the diseases described in GtoPdb. In addition, an “Immuno disease” tab links to a listing of diseases that are relevant to immunology and linked to targets and ligands in GtoImmuPdb.
The table includes the number of targets and ligands that have been associated with the disease by our curators (note, so far only the relationships between ligands relevant to immunological diseases have been formalised in the database structure, so many diseases are not yet linked up to relevant ligands/drugs).
Individual disease pages include information about the disease, such as synonyms and links to Disease Ontology, OMIM or Orphanet where available.
Targets and ligands linked to the disease are listed, with information on disease-causing mutations if known. As noted above, currently the only ligands that have been formally associated with diseases cover the immunopharmacology domain, but we hope to extend this in the future. For further details see the help documentation
The image shows part of the full disease list. The immunologically-relevant diseases are also shown under a dedicated tab.
Showing a disease summary page with links to external resources and listing the associated targets and ligands in GtoPdb/GtoImmuPdb.
Pharmacology search tool
The new Pharmacology search tool
and browser can be found under the Advanced search drop-down menu. This tool allows users to upload target ID sets to retrieve a list of ligands which modulate those targets. Detailed information on how to use it can be found in the help page
. After uploading a list of IDs (e.g. UniProtKB accessions or Ensembl gene IDs), select the number of interactions to show, and optionally, the species for the target of the interaction. By default, the results will show the top 5 interactions ordered by decreasing affinity. On the results page, the targets are ordered by how many interactions they have that match the search criteria, with 10 targets per page. A more detailed table of results (including ligand structures and affinity values) is available to download as a CSV file by clicking the “Download” button at the top of the page.
Showing a section of the results page following a Pharmacology Search. The default search returns the top 5 interactions for each target.
We’ll be extending the functionality of the tool over the next few months, so please send us your feedback and bug reports to the usual email address!
These are some of the targets which have been updated in the new release.
ATP-binding cassette transporter family
SLC22 family of organic cation and anion transporters
An update has brought our BACE1 lead inhibitors collection up to 20 with the addition of elenbecestat (E2609) and RO5508887 as clinical candidates, NB-360 with a good brain penetration and Compound 12 [PMID:28626832] as an interesting precedent of a fragment with a PDB structure. Some of these also have approximate equipotency against with BACE2. Since nearly all BACE1 inhibitors have failed clinically over the last decade (with the Merck verubecestat even having abandoned the prodromal arm) the prospects for this mechanism of action look so bleak as to challenge the central hypothesis of APP secretase target validation. Our entries now give research groups the option of direct mouse model translational comparisons between these leads in the hope of providing at least some insight into failures and possible progress.
Other new data
From time to time we select entries from relatively new journals that are including quality pharmacology papers. This release includes two examples. The first of these, the BACE1-binding fragment in PDB, is from ACS-Omega. The second, a new GtoImmuPdb S1P1 inhibitor entry, is from Pharmacology Research & Perspectives as the new Wiley/ASPET journal.
Two members associated with GtoPdb recently presented at the SAFER project kick-off meeting. The aim is to provide mechanistic insights and pharmacological tools towards safer treatments for neurological diseases focusing initially on 5-HT2A and the training of PhD students. As a proof of concept for capturing new relevant structures, we have now added a sub-nanomolar 5-HT2A inhibitor to the database.
New data in the Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb)
Since the last release at least 32 targets and 66 ligands have been added to GtoImmuPdb. The 2018.1 release also coincides with the beta 3 release of the GtoImmuPdb portal – more details of which are available in a separate blog post
. Other highlights include +20 ligands associated to immunological diseases, +1 target associated to disease, +57 targets associated to processes, and +8 targets associated to cell types.