Overview of Drug Discovery

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  • Created by: LBCW0502
  • Created on: 25-09-19 09:06
What are the factors involved when looking at a new target (starting point of small molecule drug discovery)?
Collaborations, microarrays, competitor programmes, literature, informatics, opportunistic and inspiration/creativity
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Outline drug discovery involvement
Disease - target - hits - leads - clinical candidate - drug candidate - drug
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Biologists are involved in which steps of drug discovery?
Disease and target (look at druggable targets whose activity can be modulated by high affinity ligands)
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Managers and marketing are involved in which steps of drug discovery?
Disease, clinical candidate and drug candidate (druggable diseases and targets with blockbuster potential)
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Medicinal chemists are involved in which steps of drug discovery?
Hits and leads (druggable hits and leads have drug-like structure and physicochemical properties)
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Pharmacologists are involved in which steps of drug discovery?
Clinical candidate (druggable candidates are active and safe)
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Clinicians are involved in which steps of drug discovery?
Drug candidate (druggable candidates are efficacious, useful and safe)
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Outline the period of time for drug discovery and development
A long risky road. Pre-discovery (drug discovery and pre-clinical, 3-6 years). Clinical trials (phase I/II/III, increase in number of volunteers, 6-7 years. FDA review, 0.5-2 years. Phase 4 - post-marketing surveillance
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Why do regulators attempt to abolish a project early in the process
To save money
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State features of attrition in drug discovery
Attrition rate is high. Reasons for drug failing in clinic - PK, animal toxicity, miscellaneous, adverse effects in man, commercial reasons, lack of efficacy
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What are the goals for a drug discovery programme?
Initial hits, lead compound, pre-clinical candidate, clinical candidate, drug
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Outline the medicinal chemistry strategy (1)
When formulating a drug discovery strategy, choose faster/shorter journeys and avoid slower/longer journeys. Optimising potency first and adding drug-like properties later is slower/more difficult
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Outline the medicinal chemistry strategy (2)
Starting from/staying within suitable property range gives faster progression (high potency, low dose needed, low risk of toxicity)
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State features of optimisation cycles
Many excellent ligands never become drugs. Factors considered during design and synthesis - potency/efficacy/selectivity, kinetics/metabolism/physical properties
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Why is it so difficult to make drugs?
Large number of possible drug molecules (drug discovery - work within confined area)
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What is a pharmacophore?
Part of a molecule responsible for the pharmacological effect
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Give examples of some interactions between a drug molecule and a receptor
Hydrophobic interactions, ionic bonding, covalent bonding, H bonding, pi-pi stacking (changes in the properties of the molecule can lead to loss of interactions)
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Pharmacophores are related to which two factors?
Drug activity and drug toxicity. Pharmacophore - aromatic substituent, H bonding donor, hydrophobic linker, H bonding acceptor, cationic centre. Combination of interactions maximise binding to target (activity/toxicity)
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What is Lipinski's Rule of Five?
Molecular weight <500 Da. Not more than 5 H bond donors (OH, NH). Not more than 10 H bond acceptors (O, N atoms). Octanol-water partition coefficient (log P) <5
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Describe features of drug-like vs lead-like (1)
High affinity hits (<<100mM, MW >>350, log P <3), peptide compounds and natural products, high affinity hits (activity must be retained, PK improved, difficult due to more complex core structure)
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Describe features of drug-like vs lead-like (2)
Drug-like hits (>100nM, MW>350, log P >3, compound libraries), activity improved while PK profile is maintained, activity from many poorly optimised interactions
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Describe features of drug-like vs lead-like (3)
Lead-like hits (>100 nM, MW <350, log P <3, endogenous ligands). Both activity and PK profile must be improved, now possible to introduce more lipophilic groups to improve affinity
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What is the criteria for hits (6)? -1
Reproducible in vitro affinity/efficacy. Favourable properties (cLog P, pKa, aqueous solubility, molecular weight etc.). Chemical tractability. Evidence that related compounds retain activity e.g. not a false positive
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What is the criteria for hits (6)? -2
Patentable structures/strategy to enhance chemical novelty. No significant toxicity alerts from compound or known metabolites
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State features of compound profiling
Hit to lead - lead to clinical candidates - clinical candidates to drug candidates - drug candidates to drugs. Number of chemical entities reduced through process. Biological information per chemical entity increases through process
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What is the criteria for hit to lead phase (7)? - 1
Improved affinity/efficacy. Selective over related targets (>100 fold). PPB, CYP inhibition/induction and hERG profiles acceptable. Selectivity over non-related targets. Efficacy in animal model - dose response relationship
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What is the criteria for hit to lead phase (7)? - 2
No toxicity or mutagenicity at efficacious dose. Patent strategy determined for lead compounds
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What is pharmacodynamics?
The study of the pharmacological response to a drug (what the drug does to the body)
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What is pharmacokinetics?
Study of the movement of drugs within the body (ADME) - what the body does to the drug
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Briefly outline features of ADME
Absorption (enteric transport/metabolism). Distribution (intravascular space, extravascular space, protein binding), metabolism (hepatic, phase I/II), excretion (bile, intestinal, renal)
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Describe the importance of early ADME evaluation (1)
Many factors need to be considered beyond in vitro activity. Need to build image of compounds being proposed for progression. Flag possible liabilities early to enable further investigation to take place
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Describe the importance of early ADME evaluation (2)
Problems can be engineered out if identified early. If problem persists, switch to alternative series
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Describe the importance of early ADME evaluation (3)
Look to evaluate lead compounds as early as possible in an in vivo model. Only use compound with an appropriate PK profile (negative result in vivo with compound >99.5% plasma protein bound won't tell you anything new)
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Describe the importance of early ADME evaluation (4)
Listen to casual observations made by in vivo biologists (e.g. behavioural changes, off target effects)
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What is the criteria for a pre-clinical candidate (6)? - 1
Preferred crystalline form identified. Compound sufficiently stable to allow a shelf life of >2 years. Scale up of lead compound to 100 g demonstrated. Full PK and metabolic profiling in two species. Predicted human half life and dose
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What is the criteria for a pre-clinical candidate (6)? - 2
No toxicity in extended animal study
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Outline the drug development and approval application process
Basic research (FDA interactions). Prototype design/discovery). Pre-clinical development (IND). Clinical development (phase I/II/III). FDA filing/approval and launch preparation (with safety update)
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