Drug Targets Flashcards
“EMPIRICAL’ Drug-Discovery
- Recognize initial drug lead by functionally useful effect
Examples of empirical drug discovery
- Penicillin (anti-bacterial effect);
- Taxol (anti-tumor)
- Digoxin (cardiotonic / antiarrythmic)
“RATIONAL Drug discovery
- Drug by design or screen against biochemical target’s function
Examples of rational drug discovery
- HIV-protease inhibitor (anti-infection)
- Metoprolol (anti-hypertensive)
- Methotrexate (anti-tumour)
Major causes of Drug Failure in Phase II
• Wrong target?
• Wrong patient population?
• Wrong dose?
What is a Drug Target?
A bio-molecule which either:
– Is present in the diseased tissue
– Has elevated expression in the diseased tissue
– Is overactive in diseased tissue
– Has a function contributing to development or existence of disease
– Has an involvement or role in disease process
Drug Targets and Mechanisms
- Enzymes Reversible = Irreversible Inhibitors
• Receptors = Agonists & Antagonists
• Viral Surface Proteins = Block entry into cell
• Ion channels = Block or Open channel
• Transporters = Block or promote transport
• Nucleic Acids = Inhibit function, prevent gene expression
Targets for Drug Action
- look at slide 10
What factors must pharmaceutical companies consider when developing drugs?
• Both economic and medical factors.
• They must ensure a financial return on investment.
What caused a rise in antimalarial research by pharmaceutical companies?
• Growth in tourism to exotic countries.
• The spread of malaria to regions affecting wealthier populations.
Why do pharmaceutical companies focus on diseases with few treatment options?
• To address unmet medical needs.
• To create drugs with better properties than existing ones.
• Ensures competitive advantage in the market.
What makes a good target?
- Must be differentially expressed / regulated/ located in diseased tissue
• Must be central to disease process with robust studies in clinical samples
• Must be characterised in terms of expression, activity, function and role
Why does disease-association not make a protein a viable drug target?
- The protein must be validated as a point of intervention in the disease pathway
What roles do bioinformatics and cheminformatics play in drug discovery?
• Bioinformatics: Identifies and analyzes disease-related targets using biological data.
• Cheminformatics: Helps design and optimize drug-like molecules by analyzing chemical data.
Target Validation Process
- Disease
- Target
- Target Selection
Drug Discovery Process
- Target Selection
- Leads
- Clinic
Target Validation
- Identifies and assesses whether a molecular target merits the development of drugs
- process of demonstrating that a molecular target is a therapeutically relevant pharmacological target
What is the most important part of drug discovery ?
- Target validation
A Valid Target is:
- A target that when modulated pharmacologically, provides meaningful efficacy and acceptable safety for specific human disease in long-term clinical usage
Target Validation is:
- The process of demonstrating that engaging the target provides statistically meaningful therapeutic benefit with acceptable safety for a given indication.
Proof of Concept is:
- Preclinical or limited clinical studies prior to well-powered clinical trials, that establish the scientific validity and safety of a drug target; it is part of the
continuum of target validation.
Target Identification is:
- The generation of scientific evidence that a manipulatable able target is involved in some significant way in a disease process
What is the purpose of target validation?
- Increases our confidence in the relationship between the target and the disease.
- Demonstrates target is critical or central to disease development or progression.
- Allows exploration of effects caused by modulation of target, to identify mechanism based adverse effects
Target validation of human data
- clinical experience (most important)
- genetics
- tissue expression
