From Molecule to Medicine

• How much energy is in a hydrogen bond?


  30KJ/mol per bond
• How much energy is in a vanderwaals interaction?


  2-4KJ/mol per bond
• What do proteases do?


  Proteases break down proteins. They do this by cutting the peptide bonds.
• What are important questions in drug discovery?

  is the disease widespread? does the disease effect the first world? are there drugs already on the market? what can be the competitive advantage? what about exploiting new markets?
• What are the advantages of in vivo testing?


  efficacy is guaranteed
• what are the disadvantages of in vivo testing?


  disease model is difficult to define, animals are needed, the lead optimisation is complicated and it is low throughput screening
• what are the advantages of in vitro testing?


  no animals are needed and it is high throughput screening (500000+ compounds)
• what are the disadvantages of in vitro testing?


  efficacy is not certain and molecular target does not equal hitting cause of the disease
• What is needed for HTS assay?


  it needs to be ideal (homogenous), robust, cheap, fast, reliable, reproducible (high signal-to-noise ratio and one ligand concentration is measured) and applicable to large numbers
• What do we know about the use of radioligand binding assays?


  It uses radioligands and displacers (appropriate buffer), determine [bound] and [free] radioligand (centrifugation and filtration), however they are heterogenous, radioligands are not always available, there is radioactive waste and it is expensive.
• What are different ways of biophysical screening?


  NMR screening, SPR screening, ITC screening and Virtual screening
• What are the FBDD approaches with High Throughput Screening?


  Fragment linking, fragment growing and fragment merging
• what do we know about Dynamic Combinatorial Chemistry (DCC)?


  They are reversible ligation reactions, it freezes the equilibrium to identify actives, however the analysis is difficult.
• what do we know about target-accelerated synthesis (TAS)?


  they are irreversible ligation reactions (not many bio-compatibles known yet), if signal/noise ratio is high enough, analysis is relatively simple, the method is highly specific, however it is not easy to make a universally working program.
• What is Lipinski's rule of five?


  Good oral absorption is likely when: the molecular weight <500 Da, when the Log P <5 (very hydrophobic), there are less than 5 H-bond donors and there are less than 10 H-bond acceptors.
• What are pharmacophores?


  A pharmacophore is a molecular framework that caries (phoros) the essential features responsible for a drug's (pharmacon's) biological activity. It has sterical and electronic features. It is not a molecular skeleton or body, neither is it an atom.
• What are the features of a pharmacophore?


  they are hydrophobic, aromatic, hydrogen bond acceptor/donor and negative/positive functional groups.
• Target selectivity between species?


  Antibacterial and antiviral targets
• Target selectivity within the body?


  Selectivity between receptor types and subtypes, selectivity over unrelated proteins and organ selectivity.
• How does testing drugs work?

  Tests are required to find lead compounds and for drug optimization. A combination of in vivo and in vitro tests is used in research programs.
• What is the Cheng-Prusoff equation?


  $IC50=$$(([Ki]/K(D))*$$[L])+$$Ki$
• What are different biochemical screening?

  SPA kinase assay, Functional GPCR readouts, HTS FLIPR assay (Fluorometric Imaging Plate Reader) and Calcium assay.
• What happens when a drug or poison produces a biological effect in the body?


  Then there must be a molecular target for that agent in the body. In the past this depended on finding the drug first and then the drug targets.
• Why do many potential drug targets remain hidden?


  Because many chemical messengers remain undiscovered. The advances in genomics and proteomics have changed this.
• What are orphan receptors?


  These are new targets with no lead compounds to interact with them.
• What was the driving force for the development of combinatorial synthesis and parallel synthesis?

  Orphan receptors.
• What is combinatorial synthesis?

  Method for creating large numbers of compounds by combining building blocks in various combinations.
• What is parallel synthesis?


  Simultaneous creation of multiple compounds.
• What are the best kind of targets to choose, in the field of antimicrobial agents?


  The best targets to choose are those that are unique to the microbe and are not present in humans. It is still possible to design drugs against targets which are present both in humans and the microbes, as long as the drugs show selectivity against the microbial target.
• Why should receptor agonists also show selectivity for receptor subtypes?


  The various receptor subtypes are not distributed uniformly around the body, but are often concentrated in particular tissues. However for any given function, there are usually several messengers, receptors, and enzymes that are involved.
• What is combination therapy?


  Combination therapy is usually used by administering two drugs showing selectivity to different targets.
• What is the disadvantage of combination therapy?


  The disadvantage of combination therapies is the number of different medications and the associated dose regimens.
• What are drugs that interact with a large range of targets called?


  Promiscuous ligands or dirty drugs.
• Why should a bioassay or test be simple, quick and relevant?


  There are usually a large number of compounds to be analyzed.
• What does a ‘fail fast, fail cheap’ strategy mean?


  Your efforts to create a product and find its market fit, you need to be aware you can fail.
• What is NMR spectroscopy?

  An analytical tool to determine the molecular structure of compounds. A compound is radiated with a short pulse of energy which excites the nuclei of specific atoms. the time taken by different nuclei to give off this energy is called the relaxation time.
• What are advantages of NMR spectroscopy?


  It is able to screen many compounds at the same time, able to detect weak bonds, identify the binding of small molecules to different regions of the binding sites, complimentary to high-throughput screening and can be done on a new protein without needing to know its function.
• What is Surface Plasmon Resonance?


  an optical method of detecting when a ligand binds to its target. This procedure is patented by BIAcicore and makes use of a dextran-coated, gold-surfaced glass chip. However, a component of the light called the evanescent wave penetrates a distance of about one wavelength. The evanescent wave interacts with free oscillating electrons called plasmons in the metal film.
• What is Scintillation proximity assay (PSA)?


  A visual method of detecting whether a ligands binds to a target. It involves the immobilization of the target by linking it covalently to beads which are coated with a scintillant.
• What is the evanescent waves?


  A component of the light.