Module 5: Drug discovery and Development as a process

Question 1

anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function.

Native protein in the body whose activity is modified by a drug resulting in a specific effect, which may be a desirable therapeutic effect or an unwanted adverse effect.

Answer 1

Biological target

Question 2

often referred to as a drug target

Answer 2

Biological target

Question 3

The most common drug targets:

Answer 3

Proteins
Ion channels
nucleic acids

Question 4

Most common biological targets:

Answer 4

Proteins
* G protein-coupled receptors (target of 50% of drugs)
* Enzymes (especially protein kinases, proteases, esterases, and phosphatases)
Ion channels
* ligand-gated ion channels
* voltage-gated ion channels
* nuclear hormone receptors
* structural proteins such as tubulin
* membrane transport proteins
Nucleic acids

Question 5

Decision to focus on finding an agent with a particular biological action that is anticipated to have therapeutic utility.

Answer 5

Target Identification

Question 6

It is influenced by a complex balance of scientific, medical and strategic considerations.

Answer 6

Target characterization

Question 7

Characterization of the molecular mechanisms
addressed by the target.

A good target should be _____

Answer 7

• efficacious,
• safe,
• meet clinical and commercial requirements and be ‘druggable’

Question 8

what makes a ‘good’ target?

Answer 8

1. The target has a confirmed role in the pathophysiology of a disease and/or is disease modifying
2. Target expression is not evenly distributed throughout the body.
3. The target’s 3D-structure is available to assess druggability.
4. The target is easily ‘assayable’ enabling high-throughput screening.
5. The target possesses a promising toxicity profile, potential adverse effects can be predicted using phenotypic data
6. The proposed target has a favorable intellectual property (IP) status. (relevant for pharma companies)

Question 9

Common Approaches in identifying a target:

Answer 9

Data mining using bioinformatics
Genetic association
Expression profile
Pathway and phenotypic analysis
Functional screening

Question 10

Identifying, selecting and prioritizing potential disease targets

Answer 10

Data mining using bioinformatics

Question 11

Genetic polymorphism and connection with the disease

Answer 11

Genetic association

Question 12

Changes in mRNA/protein levels

Answer 12

Expression profile

Question 13

In vitro cell-based mechanistic studies

Answer 13

Pathway and phenotypic analysis

Question 14

knock down, knockout or using target specific tools.

Answer 14

Functional screening

Question 15

Tools for Target Identification & Validation:

Answer 15

• Disease association (genetics and expression changes)
• Bioactive molecules Cell based models
• Protein interactions (pull-down assays, yeast 2 hybrid)
• Analysis of signaling pathways
• Functional analysis (overexpression, transgenics, antisense RNA, gene variants)

Question 16

Two target identification strategies:

Answer 16

Target deconvolution
Target discovery

Question 17

In this scenario you begin with a drug that appears efficacious and the target is identified retrospectively.

Answer 17

Target deconvolution

Question 18

This approach works on the concept that ‘if you want a new drug you must find a new target’, once a target is identified compound libraries are then screened to find a drug that binds to the target and elicits the desired effect.

Answer 18

Target discovery

Question 19

The phenotypic approach to drug discovery falls within the realm of _____, and involves exposing cells, isolated tissues, or animal models, to small molecules to determine whether a specific candidate molecule exerts the desired effect – which is observed by a change in phenotype.

Answer 19

target deconvolution

Question 20

• The phenotypic approach goes
  beyond individual proteins or nucleic
  acids and involves the study of entire
  signaling pathways.
• The drug’s effect is determined before
  the specific biological (drug) target
  that underlies the observed
  phenotypic response is identified

Answer 20

N/A

Question 21

Advantages and challenges of phenotypic drug
discovery:

Answer 21

• The greatest advantage of phenotypic
  approaches have over target-based is their
  ability to demonstrate the efficacy of a drug in
  the context of a cellular environment.
• The drug is acting on the target in its ‘normal’
  biological context, rather than on a purified
  target in a biochemical screen.

Question 22

• In target-based drug discovery, biological (drug) targets are already established (or ‘discovered’) before lead discovery starts – hence __________ is the cornerstone of target-based screening.
• The target’s role in a disease process is known, this target is then used to create relevant systems-based assays, and vast compound libraries are screened in search of a ‘hit’ – a candidate drug.

Answer 22

Target discovery