Conference presentation from #iccs2014 in Noordwijkerhout


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  • Is a known primary drug target an off-target for another compound so that this can be repurposed into the indication of the other one
  • Is a known primary drug target an off-target for another compound so that this can be repurposed into the indication of the other one
  • Conference presentation from #iccs2014 in Noordwijkerhout

    1. 1. The impact of large-scale genetic data on drug targets – From 1000 genomes to Drug Discovery Josef Scheiber, PhD 10th International Conference on Chemical Structures 10th German Conference on Chemoinformatics June 1-5 2014, Noordwijkerhout The Netherlands
    2. 2. Overview • General Introduction • Approaches taken with learnings and results • Further possibilities
    3. 3. Significant unmet medical need 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%  diseases Drugresponserate NSAIDS  80 % response rate Alzheimer  25 % response rate Several thousand diseases without known treatment
    4. 4. Biological/Pharmacological Understanding drugs targets pathways diseases
    5. 5. Disease understanding getting better and better 2010 1970 1960 1950 Disease of the Blood Leukemia Chronic Leukemia Acute Leukemia Preleukemia Lymphoma Indolent Lymphoma Aggressive Lymphoma Increasing understanding of underlying biology opens up new hypotheses – even/particularly for Cheminformatics! 5 Year Survival ~ 0 % ~ 70% Example: Leukemia and Lymphoma
    6. 6. From single targets to …
    7. 7. … polypharmacology to…
    8. 8. Major driver
    9. 9. … individual polypharmacology
    10. 10. The human genome contains roughly 3 billion nucleotides and the genomes of any 2 individuals vary in 3 million of them A significant likelihood that individuals respond differently to the same medicine This is rooted in differences for drug absorption, distribution, metabolism and excretion There are ~7 billion human genomes and each responds differently to drugs
    11. 11. - Cystic fibrosis caused by defects in the CFTR ion channel (orange in diagram) - Just under 5% of cases are caused by the amino acid glycine being replaced by an aspartate in position 551 of the CFTR protein - patients with this mutation are unable to transport chloride to the CFTR Why this study? A single mutation can have massive impact
    12. 12. Example: Carbamazepine/Steven Johnsons Syndrome Courtesy: Dr. Thomas Habif Why this study? A single mutation can have massive impact Difference in European and Korean populations HLA allele B*1502
    13. 13. The molecular reason behind From Wei, CY et al. Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome
    14. 14. Our large-scale analysis
    15. 15. Workflow (simplified) Call Variants for each drug target  Compare intraindividual variability with a focus on binding sites
    16. 16. Raw Data Analysis Image Processing and base calling Whole Genome Mapping Alignment to reference genome Variant Calling Detection of genetic variation (SNP, CNV etc.) Annotation Linking variants to biological information BioVariance focus Basic NGS workflow
    17. 17. Classes of structural variation Alkan, C. et al. Genome structural variation discovery and genotyping. Nature Reviews Genetics 12, 363-376 (2011). Single Nucleotide Aberrations Single Nucleotide Polymorphisms (SNPs) Single Nucleotide Variations (SNVs) Short Insertions or Deletions (indels) Larger Structural Variations (SVs)
    18. 18. Workflow Identify drug targets (primary and off-targets, from DrugBank) Call variations on a per- individuum basis
    19. 19. Workflow Analyse mutation rates in the targets and in particular drug binding pockets
    20. 20. Example: Donepezil / Acetylcholinesterase • PDB 4EY7 Image extracted from Cheung et al., 2012 [2]
    21. 21. Example: Donepezil / Acetylcholinesterase
    22. 22. Example: Acetylcholinesterase Integrative Genomics Viewer
    23. 23. Not very successful Alignment of the 3D structures of mutant number 52 (yellow) and PDB 4EY7 AChE protein (green). The only changed residue is the Y150 (magenta) to H150 (red). The white surface represents the molecular surface of donepezil.
    24. 24. Why is this a bad example? AChE a key enzyme in human biology  these are the most highly conserved, even interspecies  Learning: Look at that stuff before investing time 
    25. 25. CFTR • 1000 genomes are not enough for finding these cases
    26. 26. SLCO1B1 – Simvastatin example - Mutation 37041T>C or V174A, is a SNP in this gene, which encodes the 'organic anion transporting polypeptide 1B1' (OATP1B1) protein. - found primarily in the liver, it regulates the uptake of numerous drugs and natural compounds. The rs4149056(C) SNP defines the SLCO1B1*5 allele. - This allele described by mentioned amino acid change has reduced uptake/transport activity - Therefore, drugs metabolized by OATP1B1 tend to build up to higher circulating concentrations than they would otherwise
    27. 27. SLCO1B1 – Simvastatin example - 17fold higher probability for Rhabdomyolosis for statin patients (6fold if one allele)
    28. 28. Ultimately: An individual profile
    29. 29. What analyses are enabled? • For Drug Design: Do we work on the „right“ target and specifically on the right pocket to design compounds? • Is there a specific population where the drug will work best? • Are there off-targets that can be problematic in certain cases? • Certainly good for ligand-based approaches as well …
    30. 30. Project: Personalized Medicine for children
    31. 31. Thank you for your attention! Phone: +49 – 89 – 189 6582 – 80 Garmischer Str. 4/V 80339 Munich / Germany