Redecke

Question 1

The Definition of a Drug

Answer 1

A Drug is any substance that, when injected, inhaled,smoked, consumed, absorbed via a patch on the skin, or dissolved under the tongue, causes a physiological change in the body.

Question 2

What kind of bioaktivem molecules can be considered as drugs?

Answer 2

• small molecules
• peptides
• peptidomimetics
• protein
• oligonucleotides

Question 3

Gleevac

Answer 3

Chronic myeloid leukaemia (CML)
Inhibitor of ATP binding site of bcr-abl tyrosine kinase
Philadelphia chromosome

Question 4

Lipitor

Answer 4

Cardiovascular disease
Statin (lipid lowering agent)
HMG-coA reductase inhibitor
Bestselling drug sofar

Question 5

Taxol

Answer 5

Pacific yew tree bark extract
Ovarian and breast cancer
Stabilises microtubuli
Cell culture production

Question 6

Viagra

Answer 6

Hypertension/ erectile dysfunction
inhibition of cGMP specific phosphodiesterase
lifestyle drug

Question 7

Harvoni

Answer 7

Hepatitis C virus infection
Combination of Ledipasvir and Sofosbuvir
NS5A and NS5B inhibitors

Question 8

-mabs

Answer 8

monoclonal antibodies eg. Adalimumab, Infliximab (immune suppressor TNF-a)
autoimmune disorders

Question 9

Paul Ehrlich

Answer 9

-conceived many of the key elements of modern drug discovery
-salvarsan 1. cure for syphilisis
-from organic dyes to first discovered resistance rugs
recognition of chemicals for therapy - targeted chemotherapy
used synthetic chemistry to make derivates with different activities
recognized that metabolism could modify chemicals internally - active metabolite concept (pro drug)

Question 10

Prontosil

Answer 10

Azo dye that becomes wold first broad-spectrum anti-biotic

Question 11

What is rational drug design?

Answer 11

Rational (mechanism-based) drug discovery first identifies a key molecular target (drug-receptor) that is important in the disease process

Question 12

How do molecules act that are interesting for rational drug discovery?

Answer 12

• Block BINDING of endogenous ligand
• Inhibit ACTIVITY of the target
• Alter EXPRESSION of the target
• Alter INTERACTION of the target with other molecules

Question 13

Name the steps of rational drug discovery

Answer 13

1. Disease selection
2. Target identification
3. Lead compound identification
4. lead compound optimization
5. Pre-clinical trials
6. Clinical trials

Question 14

Name characteristics of a good target

Answer 14

A good target..
-is efficacious and save
-meets clinical and commercial needs
-is druggable (accessible to putative drug molecules)
-has specific binding sites
-may change its biomolecular structure upon small molecule binding
-induces a physiological response by structure change on cell, organ or body level
-phsycological responses have therapeutic effect on pathological conditions
BUT
-drug targets are also involved in physiological processes
-complicated diseases - many different drug targets in a disease
-drug targets can change
drug might have more then one target

Question 15

Target identification methods

Answer 15

• Data mining: Use of bioinformatics and databases (genomics, transcriptomics, proteomics, structures, literature, etc.)
• Structural genomics: sequence-structure homology recognition (fold recognition)
• Cell or animal models: studying the disease (tumor cell line, diabetic mice..)

Question 16

Target validation

Answer 16

-> verifying the role in the disease
-defining the role of the target in the disease
-identifying patient populations susceptible to intervention using the target
-performing experiments in a cellular system to confirm that regulation of the target or downstream effects have the expected effect
=> Target validation confirms that interactions with the target produce the desired change in the behaviour of diseased cells

Question 17

Assay development

Answer 17

Screening = Filtration of active molecules against a target from a huge library

• enable characterization of novel compounds and obtain the potency of these compounds against the target in question
• robot-assisted HTS

Question 18

Strategy lead discovery/ optimization:

Pros and cons of High-throughput screening (HTS)

Answer 18

\+ 
no structural info needed
robot-assisted
libraries of compounds
-
enormous chemical space
false positive hits
expensive

Question 19

Strategy lead discovery/ optimization:

Pros and cons of virtual screening

Answer 19

\+
structure-guided optimization
low costs
fragment libraries
-
computational capacity
adequate scoring factor
based on predicted interactions

Question 20

Strategy lead discovery/ optimization:

Pros and cons of Structure based drug discovery (SBDD)

Answer 20

\+
structure-based optimization
fragment libraries
no false positive
low binding affinities
-
requires crystal of protein complex
high-throughput screening?
expensive