Drug discovery now

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Questions and Answers

Which characteristic is essential for a good drug target?

Low molecular weight compounds can easily modulate it (correct)

It primarily expresses on tissues unrelated to the disease

It causes off-target effects on other tissues

It must be solely composed of one binding site

What is a critical factor in determining the economic viability of drug development?

Cost of laboratory testing

Duration of the clinical trials

Presence of rival medications

Market size of the target population (correct)

What does 'druggability' refer to in drug discovery?

The target's ability to resist any drug interaction

How likely a target can be modulated by compounds with 'drug-like' properties (correct)

The number of toxic side effects associated with the target

The ease of synthesizing the drug compounds

Which factor decreases the feasibility of drug development for certain diseases?

The complexity of the disease pathway Signup and view all the answers

What is the significance of having assays available for high-throughput screening?

They facilitate the rapid testing of numerous compounds against the target Signup and view all the answers

Why is a small drug with one target considered a better target in drug discovery?

It has a lower risk of adverse effects Signup and view all the answers

Which of the following factors does NOT contribute to the potential for adverse effects in target-based drug discovery?

Known structure of the target protein Signup and view all the answers

What is the primary goal of target identification in drug discovery?

To verify the target's role in disease pathogenesis Signup and view all the answers

In target-based drug discovery, what typically happens after target validation?

Assays are developed for screening compound libraries Signup and view all the answers

Which of the following best describes high-throughput screening?

Utilizes biochemical or cellular assays to evaluate large libraries Signup and view all the answers

Why might it be important to assess physicochemical properties in drug discovery?

To ensure compounds have minimal side effects Signup and view all the answers

What does the term 'druggable genome' refer to?

Genes that can be targeted by drugs Signup and view all the answers

What is a potential benefit of using structure-based drug design?

It can lead to more cost-effective drug discovery Signup and view all the answers

Which gene number is generally associated with disease-modifying genes?

Approximately 3,000 Signup and view all the answers

In the context of drug development, why is toxicity testing crucial?

To avoid adverse effects and ensure safety Signup and view all the answers

What is often a challenge in target identification for polygenic diseases?

It requires extensive understanding of genetic interactions Signup and view all the answers

What is included in the IND dossier submitted to the FDA?

Pharmacological profile and toxicity profile Signup and view all the answers

Which of the following best describes the purpose of toxicity testing?

To evaluate side effects from prolonged use Signup and view all the answers

Which drug's withdrawal led to the establishment of mandatory teratogenic potential testing?

Thalidomide Signup and view all the answers

In pharmacological characterization, what does ADME stand for?

Administration, Distribution, Metabolism, Excretion Signup and view all the answers

Which aspect of preclinical development is primarily assessed using animal studies?

Toxicity and dose-response relationship Signup and view all the answers

What defines the length of chronic toxicity study exposure?

Depends on intended clinical use Signup and view all the answers

Which of the following is NOT generally a component of the pharmacological profile?

Market share analysis Signup and view all the answers

What is the primary focus of systematic and hierarchical toxicity testing?

To address acute effects before chronic effects Signup and view all the answers

Which type of study is essential before human testing to understand potential toxicity?

Testing in both rodent and non-rodent species Signup and view all the answers

Study Notes

Choosing Disease

Unmet medical need: A serious condition with inadequate existing therapy.
- Serious: Health is deteriorating.
- Inadequate: Drugs are resistant or have significant adverse effects.
Economic viability: Factors to consider include target population size, purchasing power, and feasibility of drug development.
- Target population size: Larger populations create larger markets and better economic returns for companies.
- Purchasing power: Lower in low- and middle-income countries.
- Feasibility of drug development: Lower risks draw more funding and attract more investment.
- Orphan diseases: Pose additional challenges due to smaller market sizes. The definition of "orphan" varies across countries.

What Makes a Good Drug Target?

Directly participates in the disease's pathophysiology.
Primarily expressed in the target tissue to avoid adverse effects on other tissues (off-target effects).
Has a known 3D structure.
Druggable: Can be modulated by low molecular weight compounds to achieve the desired effect.
Requires readily available assays for high-throughput screening or the ability to develop such assays.

Druggability

Likelihood that a target can be altered by low molecular weight compounds with 'drug-like' properties.
- Drug-like properties: Oral activity, bioavailability, high affinity, and potency.
- High potency minimizes the potential for adverse effects.
Can be predicted by:
- Structure and endogenous ligand information:
  - Small drugs with one target are ideal.
  - Large proteins with multiple binding sites are less desirable.
- Information about target protein family:
  - Have similar proteins been successfully targeted previously?
Druggable genome: Approximately 3,000 out of 20,000-22,000 protein-encoding genes in the human genome.
Drug targets: Estimated to be between 600-1500.
Disease-modifying genes: Around 3,000.

Target Identification and Validation

Evidence: Target's involvement in disease pathogenesis and evidence that modifying the target affects disease state.
Understanding of disease molecular mechanisms: Essential.
Process: May be straightforward for monogenic disorders but more complex for polygenic diseases.
- Monogenic disease example: The C-C gene in cystic fibrosis.
Big data utilization: Examining gene upregulation and downregulation during disease progression.

Assay Development - Screening - Hits & Leads

Target-Based Drug Discovery

Assay development for high-throughput screening: Often biochemical or cellular assays.
Screening:
- Large small molecular libraries are expensive.
- Focused libraries can be aided by structure-based drug design or ligand-based design, making them more cost-effective.
Hit and lead identification:
- Confirmation of chemical hits.
- Assessment of physicochemical properties and selectivity (often in silico).
- Determining pharmacodynamic parameters like potency, toxicity, and selectivity.

Target-Based vs Phenotype-Based Drug Discovery

Target-based drug discovery:
- A target is identified and validated.
- Assays are developed to screen compound libraries to identify hits.
Phenotype-based drug discovery:
- A compound eliciting a desired phenotype is identified.
- The target is identified retrospectively.
- No need to know the target mechanism; it is determined after identification.
- Predominant before the complete sequencing of the human genome.

Preclinical Development & IND Dossier information

IND (Investigational New Drug) dossier: Submitted to the FDA for approval of clinical testing.
Information includes:
- Toxicity profile: In vitro, ex vivo, and in vivo data.
- Pharmacological profile: In vitro and in vivo data, focusing on pharmacodynamic and pharmacokinetic parameters (ADME), dose, frequency, and route of administration.
- Chemical/manufacturing information: Composition and source of natural products.
- Formulation: Combination of drug substance with other substances for optimal administration, compliance, stability, and shelf life.
- Proposed clinical plans/protocols.
- Dose and route of administration: Determined using animal models before human testing to understand toxicity.

Toxicity Testing

Systematic and hierarchical approach: From in vitro to ex vivo to in vivo, using rodents and primates.
Acute toxicity: Effect of a single high dose.
Chronic toxicity: Effect of long-term exposure (6-24 months).
Length of study: Depends on the intended clinical use.

Unsafe Drugs & the Importance of Toxicity Testing

Thalidomide: Initially indicated for morning sickness.
Teratogenicity: Led to malformed infants.
Regulatory landscape changes:
- Mandatory testing for teratogenic potential.
- Previously, testing was not mandatory or regularly performed.
Current requirements: Testing in at least one rodent and one non-rodent species before human trials.

Characterizing Pharmacological Profiles

Systematic and hierarchical approach: From in vitro to ex vivo to in vivo, using rodents to primates.
Pharmacological assays: Should reflect the disease being studied.
Safety assessment: Identifying pharmacodynamic effects on physiological functions.
Adverse effects:
- Predictable:
  - Related to the mechanism of action on the desired target or unintended tissues (off-target).
  - Related to the chemical class's off-target effects.
- Unpredictable:
  - Unrelated to the mechanism of action.

Clinical Trials

Purpose: Testing compounds in humans to determine tolerability, effectiveness, adverse effects, and potential beneficial effects.
Phases:
- Phase 1: Small group of healthy volunteers (20-80).
- Phase 2: Larger group of healthy volunteers or patients with the disease (several hundred).
- Phase 3: Large number of patients with the disease (several hundred to several thousand).
- Phase 4: Drug is approved and tested in the general population.
Important Considerations:
- Phase 1:
  - Not always performed with healthy volunteers, especially for drugs like chemotherapy.
  - Aims to assess safety, tolerability, and appropriate dose.
- Phase 2:
  - Assess effectiveness and further evaluate safety.
  - Determine optimal dose and frequency.
- Phase 3:
  - Large-scale evaluation of effectiveness, safety, and comparison to existing treatments.
- Phase 4:
  - Continued monitoring of safety and effectiveness in a real-world setting.
- Interpatient variability: More pronounced in Phase 4 due to the broader population.
Overall Goals:
- Is the drug safe?
- Is the drug effective?
- What are the adverse effects?
- Can rare adverse effects be identified in larger populations?
Focus:
- Phase 1: Tolerability and safety.
- Phase 2: Effectiveness and dose optimization.
- Phase 3: Effectiveness compared to standard treatment.
- Phase 4: Continued safety and effectiveness monitoring.
Data:
- Provides valuable information regarding the drug's effectiveness in the target population and uncovers rare adverse events.

Important Drug Information Before Clinical Trials

Side effects and toxicity: Must be thoroughly assessed.
Drug-drug interactions: Identification and management are essential.
Efficacious dose: Required to achieve therapeutic benefits.
Bioavailability: Amount of drug reaching systemic circulation.
Lipid solubility: Affects distribution and absorption.
Half-life: Time taken for the drug to reach half its initial concentration in the body.
Volume of distribution: Extent of drug distribution in the body.
Metabolism: Process of drug breakdown in the body.

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Description

Explore the critical factors in selecting diseases for drug development. Understand the unmet medical needs and the economic viability of targeting specific conditions. This quiz focuses on the criteria that define effective drug targets and the complexities of orphan diseases.