Drug Discovery and Targeting

• Medicinal chemistry: the science that deals with the discovery and design of new therapeutic chemicals and their development into useful medicines.
• Medicine: a substance or mixture of substances used to treat or prevent a disease.
• Drug: a molecule which affects biological processes.
• Disease: an abnormality in an organism. A disorder of structure or function not resulting from physical injury.
• Curative: cure an existing condition e.g., infectious diseases, emergency medicines.
• Palliative: reduce or east the severity (control) e.g., diabetes, cancer.
• Preventative: prevent a future disease.
• There are several types of medicines:

  • Small molecules
  • Biologics
  • Oligonucleotides
  • Complex medicines
• Drug nomenclature is dependent on certain moieties present in the drug.

  
• Lead identification: screening, hit conformation, hit-to-lead chemistry
• Lead optimisation: optimisation for activity, selectivity, ADMET, in vivo proof of concept
• Clinical phase I: clinical trials with dozens of healthy volunteers, with outcomes of safe clinical candidate with acceptable PK and dosing.
• Clinical phase II: clinical trials with hundreds of patients, resulting in safe candidate with efficiency.
• Clinical phase III: large scale clinical trials with thousands of patients, confirming efficacy and safety NDA filing.
• ADMET: adsorption, distribution, metabolism, excretion and toxicity.
• New drug application (NDA): based on clinical trials, required before widespread use of a new drug.
• Investigational new drug (IND): first phase of drug approval, allowing subsequent clinical trials.
• Food and drug administration (FDA): US federal body responsible for assessing drug development data and safety approval.
• Pharmacokinetics: what metabolism does to the drug.
• Pharmacodynamics: the biochemical and physiologic effects of a drug.
• Target/molecular target: proteins or other biomolecules to which the drug directly binds, which are responsible for the therapeutic effect of the drug.
• Targets at a molecular level:

  • Receptors
  • Ion channels
  • Enzymes
  • DNA/RNA
  • Cell wall/membrane
• Target validation:

  • Will inhibiting this target work?
  • Reduce expression of protein to assess involvement/toxicity
  • Knock-out: gene removed
  • Knock-in: gene replaces with a non-functional mutant
  • Knock-down e.g., siRNA (triggers degradation of mRNA of target protein)
• A good binding pocket tends to be:

  • The right size to accommodate a drug-sized molecule
  • Buried: increases surface area available for interactions
  • Not too polar - polar molecules aren't easily absorbed and are easily excreted
• In vitro human targets: disease models in cells, can delete or over express gene.
• In vivo human targets: disease models in multicellular organisms such as yeast or C. elegans.
• Lead compounds may come from:

  • Natural products such as plants, animals, microorganisms, and marine organisms
  • Target's natural substrate (hormones, neurotransmitters, enzyme substances)
  • A marketed drug/published inhibition/ side-effect
  • In silico (computational medicinal chemistry)
• High-throughput screening (HTS)

  • Test many compounds
  • Miniaturised assays
  • Parallel screening in plates
  • Can be automated, variety of readouts
  • e.g., UV-vis, fluorescence, radioactivity
• There are three classes of HTS assays:

  • Cell-based (complex pathways)
  • Enzyme (inhibitors/activators)
  • Receptor (agonsits/antagonists)
• Once optimisation is complete, the drug moves into development:

  • Clinical phase I is used to determine human pharmacokinetics and type of administration
  • Clinical phase II is used to determine efficacy with further measurements on pharmacokinetics, side effects, tolerance and dosing regimen
  • Clinical phase III is used to decide dosing regimen, with safety and efficacy carefully evaluated and compared with existing standard of care
• Clinical phase IV studies: to determine low incidence side effects of a new drug (< 1%).
• Repositioning: discovery of additional clinical indications e.g., Viagra was developed for angina, now marketed for erectile dysfunction and now used for hypertension.
• Clinical switching: single stereoisomer of existing racemic drug.
• Combinations: improve patient compliance e.g., Avandia combination of two antidiabetic drugs (withdrawn 2010 - 2011).
• Reformulation: less frequent dosing or reduction in toxicity e.g., Doxil - liposomally encapsulated form of doxorubicin.
• Enzymes:

  • Provide reaction surface and a suitable environment
  • Bring reactants together and position them correctly so that they can easily attain their transition state configurations
  • Weaken bonds in the reactants
  • May participate in the mechanism
  • Form stronger interactions with the transition state than with the substrate or the product
• The amino acids in an active site can bind to the substrate or cofactor to allow participation in the reaction mechanism.

  
• Methotrexate: a chemotherapy agent. Acts as a competitive inhibitor of the folate pathway, preventing cell growth and division.

  
• Dihydrofolate reductase (DHFR) is an enzyme that catalyses the reaction of 7,8-dihydrofolate and NADPH to form 5,6,7,8-tetrahydrofolate and NADP+. THF is essential for synthesis of purines, thymidylate and amino acids. Affinity of methotrexate for DHFR is about 1000-fold increase compared to DHF.

  
• Orlistat: irreversible enzyme inhibitor that acts on pancreatic lipase. Binding causes conformational change that exposes the serine residue.