Week 2

• The drug discovery process consists of seven main phases: target identification/selection, target validation, lead discovery, lead optimisation, preclinical development, regulatory approval, and clinical development.
• Drug discovery costs approximately £1.5bn and takes over 10-15 years.
• The consequences of failed regulatory approval can be severe, as seen in the case of Motif Bio's Iclaprim, an antibiotic for bacterial skin infections, which was denied New Drug Application (NDA) by the FDA based on liver toxicity concerns.
• Lack of efficacy often detected in phase 2 clinical trial, unexpected toxicity, risk outweighs benefit, poor target cell uptake, off target binding, lack of funding are factors that contribute to drug failures.
• Novelty in drug discovery can be achieved by targeting a new target for a specified illness, an existing target for a different illness, developing a new compound with improved efficacy/reduced adverse drug reactions (ADR), altering the route of administration/frequency of dosing, or by targeting RNA.
• Classes of drugs on the market include small molecules (SMOLs) which target proteins (enzymes/receptors/ion channels), and biologics (peptides/antibodies) which target extracellular proteins and cell surface receptors.
• Phenotype or target based approach in drug discovery can be either phenotype based approach, where the identity of the drug target is unknown and substances are characterized on their physiological effects in disease assays, or target based approach, where a drug is developed for a known target.
• Target identification/validation is a crucial step in drug discovery.
• The drug discovery process consists of several main phases: target identification/validation, hit and lead compound identification, and clinical development.
• An ideal drug target has specific properties such as being specific, selective, and having a high affinity for the target.
• High throughput screening (HTS) is a crucial part of the drug discovery process, and various techniques are available for GPCR target screening.
• The processes/criteria for progressing hit and lead compounds for clinical development involve in vitro and in vivo (animal/human) involvement of the target.
• Target druggability describes a target that is known to or at least predicted to bind to drug with high affinity.
• Screening assays generally rely on stable cell lines which have been transfected to over-express target of interest (ion channels, transporters, antibacterial activity, proliferation), allowing assessment of compounds on cell viability/proliferation/metabolism/cytotoxicity/signal transduction.
• Off-target effects are a potential issue in screening assays.
• Test compounds that compete for the target (binding site) in SPA displace the radioligand.
• Scintillation Proximity Assay (SPA) involves a SPA bead containing scintillant which emits light when in close proximity to ionising radiation.
• Fragment screening involves using small molecular weight compounds that bind weakly to the target (μM to mM), allowing these fragments to be 'built up' so they possess enhanced affinity.
• Permeability/transporters refers to the ability of a test compound to reach the target.
• Biochemical assays generally rely on over expression and purification of target protein, and use a cell free system to quantify/study the interaction between enzyme/substrate, receptor/ligand, protein/protein.
• Immortalised/primary/stable cell lines are used within drug discovery, and have advantages/disadvantages.
• There is no preferred cell line within drug discovery.
• If a drug fails to produce therapeutic effect (efficacy), it can rule out the drug not binding to target in vivo.
• Target engagement can also be measured, with full engagement potentially leading to side effects and fractional occupancy potentially reducing side effects.
• Target engagement involves the binding of ligand to receptor.
• Target engagement can be useful if a drug has desirable phenotypic responses but unknown target.
• Lead optimisation aims to enhance the most promising compounds by improving efficacy, potency, selectivity, PK and reducing toxicity/side effects.
• Target engagement can establish the validity of a given target.
• Compound screening can involve high throughput screening, which is the most common method, or focused screen, where subsets of molecules are selected based on previous data, such as drugs targeting kinases.
• Cell type distribution can vary amongst different mouse strains.
• Intellectual property, including patent, is crucial in drug development, with patent taking approximately 18 months to publish and being imperative that nothing has been stated in a public form otherwise patent unobtainable.
• Animal models of disease are used to test lead compounds in vivo, considering factors such as the need to choose appropriate model, model fully replicating human disease, and shared pathophysiology.
• Lead compounds should interact with the target with the intended mechanism.
• Without intellectual property, it is difficult to reach commercialisation and investor returns.
• Cell membrane damage can lead to loss of signal.
• Lead compounds should reach the intended site of action.
• A pharmacophore is a region of a compound that is responsible for binding to the receptor.
• Potential for intellectual property, lead molecule is reasonably potent, and it binds to close relatives such as 5HT receptors.
• Use organ bath pharmacology to assess vascular reactivity.
• Alterations in where the alcohol group (OH) is situated can affect the potency of a compound.