www.guidetopharmacology.org
Alzheimer’s in GToP
Front-loading clinical ligands and targets to be
retrievable by a major di...
Objectives
• Take a sweep through the reviews for a snapshot of AD
clinical candidates
• Resolve these to structures, mole...
Sources
3
Curatorial Challenges
• Most reviews and lists were not curation-friendly
• Blinding of lead structures (e.g. for BACE1 )
...
Results I
• http://guidetopharmacology.org/GRAC/LigandTextSearchForward?page=4
&searchString=Alzheimer&searchCategories=al...
Results II
6
Target Example: BACE1
7
Clinical Example:LY2811376
8
Social Media as a Curation Source
9
Going Forward
• Publicise
• User feedback and committee crowdsourcing
• Fill in remaining mmoa gaps
• Extend patent mappin...
Questions ?
11
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Alzheimer’s in the Guide to PHARMACOLGY: front-loading ligands and targets

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A presentation made at the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) Joint Meeting with the British Pharmacological Society and the Editors of ‘The Concise Guide to PHARMACOLOGY’ (April, 2014, Edinburgh University)

Results can be directly acessed via the following link:

http://guidetopharmacology.org/GRAC/LigandTextSearchForward?page=4&searchString=Alzheimer&searchCategories=all&order=rank

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Alzheimer’s in the Guide to PHARMACOLGY: front-loading ligands and targets

  1. 1. www.guidetopharmacology.org Alzheimer’s in GToP Front-loading clinical ligands and targets to be retrievable by a major disease term Chris Southan, Edinburgh Meeting, April 2014 1
  2. 2. Objectives • Take a sweep through the reviews for a snapshot of AD clinical candidates • Resolve these to structures, molecular mechanisms of action (mmoas), protein targets and citable activity data • Curate these into the database • Explore optimisations and issues • Assess utility for AD, other diseases and tagged collections 2
  3. 3. Sources 3
  4. 4. Curatorial Challenges • Most reviews and lists were not curation-friendly • Blinding of lead structures (e.g. for BACE1 ) – E2609, PF-05297909, HPP854, RG7129, AZD3293, CTS-21166, MK-8931 – journals violating principle of reproducibility – may find key structure clues in patents, but not easily • Unknown or indirect mmoas – alpha secretase stimulation • Surfacing of development and clinical data largely ad hoc – no pointers from clinicaltrials.gov to PubMed – results in either, both or neither and with poor comparability – date leap-frogging between clinicaltrials.gov, press releases and papers • Difficult to interpret, distil and standardise author semantics to insightful free-text curator comments e.g. – why is this compound not being progressed for AD? – what did “termination” in this clinical trials.gov record mean? 4
  5. 5. Results I • http://guidetopharmacology.org/GRAC/LigandTextSearchForward?page=4 &searchString=Alzheimer&searchCategories=all&order=rank • 39 ligands with an eclectic mix of mmoas – two imaging reagents – four anti A-beta peptide antibodies – Cognition enhancers and secretase inhibitors in the majority • Unfortunately, nothing that would classify as “successful” against the underlying pathology • Old targets e.g. the cholinesterases (ACHE, BCHE) • New targets e.g. Corticosteroid 11-beta-dehydrogenase (HSD11B1) • Usual suspects e.g. beta and gamma APP secretases (BACE1, PSEN1) • Unexpected targets e.g. LpPLA2 (PLA2G7) • Repurposing attempts e.g. Liraglutide (diabetes) and Bepridil (vasodilator) 5
  6. 6. Results II 6
  7. 7. Target Example: BACE1 7
  8. 8. Clinical Example:LY2811376 8
  9. 9. Social Media as a Curation Source 9
  10. 10. Going Forward • Publicise • User feedback and committee crowdsourcing • Fill in remaining mmoa gaps • Extend patent mapping for SAR data sets not in the literature • Keep on top of new clinical candidates • Extend research level capture for new mmoas • Assess current query recall and specificity (e.g. targets vs ligands) • Assess future disease ontologies for query recall • Explore general meta-tagging options such as: – European College of Neuropsychopharmacology (ECNP) – “repurposed” or (available for) “repurposing” (NCATS, AstraZeneca/MRC) – Company portfolios • Lobby for clinical trial structure un-blinding and data transparency 10
  11. 11. Questions ? 11

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