An overview of drug discovery


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One of the lectures that I did for the graduate students at USP São Carlos . The photograph in the title slide was taken in Asunción.

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An overview of drug discovery

  1. 1. An Overview of Drug Discovery Peter W Kenny (
  2. 2. Some things that are hurting Pharma • Having to exploit targets that are weakly-linked to human disease • Inability to predict idiosyncratic toxicity • Inability to measure free (unbound) physiological concentrations of drug for remote targets (e.g. intracellular or within blood brain barrier) Dans la merde:
  3. 3. [𝐷𝑟𝑢𝑔 𝑿, 𝑡 ] 𝑓𝑟𝑒𝑒 𝐾 𝑑 Why is it drug discovery and not drug design?
  4. 4. In tissues Free in plasma Bound to plasma protein Dose of drug Eliminated drug A simplified view of what happens to drugs
  5. 5. Drug discovery process Lead Identification (LI) Target Hypothesis Lead Optimisation (LO) Clinical development
  6. 6. Looking for leads: An overview of screening Chemical Space Leads High throughput screening Virtual (directed) screening Hit to lead Fragment screening
  7. 7. Another view of HTS
  8. 8. • Every assay has a dynamic range outside which the response cannot be quantified • Power of an assay power can be defined by weakness of binding that can be reliably quantified Assays
  9. 9. Screening and Chemical Space
  10. 10. Measures of Diversity & Coverage • • • • • • • • • • • • • • • 2-Dimensional representation of chemical space is used here to illustrate concepts of diversity and coverage. Stars indicate compounds selected to sample this region of chemical space. In this representation, similar compounds are close together
  11. 11. The neighborhood concept
  12. 12. The (slightly modified) Hann molecular complexity model This model is equally relevant to conventional and fragment-based screening. See Hann, Leach & Harper J. Chem. Inf. Comput. Sci., 2001, 41, 856-864 | Molecular complexity Probability P[fit] P[detect|fit] P[lead]
  13. 13. Degree of substitution as measure of molecular complexity The prototypical benzoic acid can be accommodated at both sites and, provided that binding can be observed, will deliver a hit against both targets See Blomberg et al JCAMD 2009, 23, 513-525 | | This way of thinking about molecular complexity is similar to the ‘needle’ concept introduced by Roche researchers. See Boehm et al J. Med. Chem. 2000, 43, 2664-2774 |
  14. 14. Hopkins, Groom & Alex, DDT 2004, 9, 430-431 Ligand Lipophilicity Efficiency LLE = pIC50 - ClogP Leeson & Springthorpe , NRDD 2007, 6, 881-890. Measured binding is scaled Measured binding is offset Binding Efficiency Measures Ligand Efficiency LE= DGº/NonHyd
  15. 15. FBDD Essentials Screen fragments Synthetic Elaboration Target Target & fragment hit Target & lead
  16. 16. Link Fragment Elaboration Tactics Merge Grow
  17. 17. • Control of properties of compounds and materials by manipulation of molecular properties Molecular Design
  18. 18. Hypothesis-Driven Framework in which to assemble SAR/SPR as efficiently as possible Prediction-Driven Assumes existence of predictive models with required degree of accuracy Molecular Design
  19. 19. Molecular Recognition • Framework for design hypotheses • Functional behavior of molecules is determined by the interactions of its molecules with the different environments in which they exist • Mutual presentation of molecular surfaces • For association in water we need to match interaction potential to maximise affinity
  20. 20. Molecular Interactions and Drug Action
  21. 21. -0.316 -0.315 -0.296 -0.295 Bioisosteric relationship: Carboxylic acids and tetrazoles JCIM, 2009, 49, 1234-1244 -0.262 -0.261 -0.268 -0.268 Molecular electrostatic potential minima (Vmin; electronic units) shown for acetate and 5-methyltetrazole anions
  22. 22. Cartoon representation of hydrophobic effect Polar Surface Binding Pocket
  23. 23. Cartoon representation of hydrophobic forces
  24. 24. Molecular Size Lipophilicity Ionisation (pKa) Solubility Metabolic stability Off-target activity (e.g. CYPs, hERG) Volume of distribution Permeability Active transport Property-based design Plasma protein binding
  25. 25. Lipophilic & half ionised Hydrophilic Introduction to partition coefficients
  26. 26. Octanol/Water Alkane/Water Octanol/water is not the only partitioning system
  27. 27. Does octanol/water ‘see’ hydrogen bond donors? --0.06 -0.23 -0.24 --1.01 -0.66 Sangster lab database of octanol/water partition coefficients: --1.05
  28. 28. P O O O F F P O O O F F 15M Inactive at 200M N S N O O O N S N O O O OMe N S N O O O N S N O O O OMe AZ10336676 3 mM conformational lock 150 M hydrophobic m-subst 130 M AZ11548766 3 M PTP1B: Fragment elaboration Elaboration by Hybridisation: Literature SAR was mapped onto the fragment AZ10336676 (green). Note overlay of aromatic rings of elaborated fragment AZ11548766 (blue) and difluorophosphonate (red). See Bioorg Med Chem Lett, 15, 2503-2507 (2005)
  29. 29. Effect of bioisosteric replacement on plasma protein binding ? Date of Analysis N DlogFu SE SD %increase 2003 7 -0.64 0.09 0.23 0 2008 12 -0.60 0.06 0.20 0 Mining PPB database for carboxylate/tetrazole pairs suggested that bioisosteric replacement would lead to decrease in Fu so tetrazoles not synthesised. Birch et al, BMCL 2009, 19, 850-853
  30. 30. Some things to think about… • Drug discovery: – Sampling chemical space • Molecular design: – Tuning interaction potential of molecules • Free concentration of the drug is also important
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