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What is the pathway for drug discovery?
biology 1 - finding a target
HTS - assay is developed to see if it can be modulated
MedChem and DMPK - optimising molecules and looks at hits and sees if they are biologically compatible
Biology 2 - drug candidates are tested for toxicity, formulation, how to administer
Clinical trials 1,2,3
What percentage of drugs makes it through clinical trials?
only 10% due to efficacy and toxicology issues
What is a diagram showing causes of death?
Lots of diseases are self inflicted
Where are all drugs used in medicine today developed from?
lead compounds discovered in numerous ways
What are some different ways drugs were discovered?
Ethnopharmacology, screening of natural sources, combinatorial methods e.g., hts, virtual screening, serendipity
What is a diagram showing drug distribution types?
most are synthetic
What is serendipity?
Chance discoveries that have been exploited with sagacity
Why aren’t all lead compounds used as drugs?
Not active enough, have serious/undesired side effects and aren’t easily administered to patients so not orally active
What can be altered in a lead compounds discovered?
Structural changes can alter pharmacological action and improve activities/remove side effects
What does the lead structure provide?
a basis for design of new drugs e.g., salicylic acid from white willow used to make aspirin
What is neighbourhood behaviour?
Structurally similar molecules tend to have similar properties e.g., morphine, codeine and heroin which are all addictive
What is structure activity relationship?
Correlation of structure with biological activity
What happens in an SAR study?
A number of compounds are made which vary slightly from the original and the biological activity of each is determined
What is the aim of SAR studies?
determine which parts of the lead molecule are essential for biological activity and which parts cause undesired side effects
Develop an analogue of the lead compound that has the best combination of therapeutic properties
What is an example of the drug discovery programme based on the SAR approach?
Cure for sphyilis - Salvarsan cures sphyilis and is less toxic but original lead was atoxyl
What is a pharmacophore?
identifying all important binding groups in the lead compounds and contains only the relevant groups that interact with a receptor and are responsible for the activity
How are SARs used to determine pharmacophores?
identifying a lead structure
Identifying a possible drug target binding groups
Synthesis of a series of analogues where 1 binding group is removed
Test all analogies for biological activity
Identification of pharmacophore
What do you look at when a single binding group is modified or removed in SAR?
If bio activity is lower we know the functional group is key and all analogues must contain it
What are the 3 ways potential binding groups bind to a target?
H bonding - groups possessing electron deficient hydrogens e.g., hydroxyl, amino groups
Ionic binding - groups that can form cations or anions e.g., amino groups
Van der Waals/hydrophobic - important for hydrophobic groups that lie close to and interact with hydrophobic groups in a target e.g., aromatic rings, double bonds
What are biochemical assays?
based on protein/biomolecule - IC50
What are cell-based assays?
germination half-inhibition concentration - GC50
What equations link to assays?
Gibbs free energy and dissociation constant
What are the 3 key points about ligand affinity?
Ligand hydrophobicity gives affinity, hydrogen bonding gives specificity
High-affinity ligands bind in low energy confirmations
Biochemical systems exhibit enthalpy-entropy compensation, where increased bonding is offset by an entropic penalty and reduces magnitude of change = affinity
