Lead Identification and Optimization

Question 1

Who is known as “The Father of Microbiology”?

Answer 1

Anton van Leeuwenhoek

He was the first person to identify bacteria via microscopy.

Question 2

What did Louis Pasteur do?

Answer 2

He developed the link between bacteria and disease.

Question 3

What did Koch do?

Answer 3

He identified the micro-organisms for anthrax, TB, cholera, and typhoid.

Question 4

What did Lister do?

Answer 4

He helped create the “germ theory of disease”. He used carbolic soap to prevent infections during his surgeries. He was a pioneer of antiseptic surgery.

Question 5

What did Ehrlich do?

Answer 5

He coined chemotherapy.

He used synthetic chemicals to try and cure disease.

Question 6

Who had the proponent of the “Magic Bullet”?

Answer 6

Paul Ehrlich. He aimed to use chemicals to treat disease.

Question 7

What was the first fully synthetic drug?

Answer 7

Salvarsan. It contained 605 arsenic containing compounds. It wasn’t good against bacteria, but was good against sleeping sickness and syphilis.

Question 8

What are 5 drug targets for small molecules?

Answer 8

Enzyme
Receptor
Nucleic Acid
Ion Channels
Transporters

Question 9

How can a drug be validated?

Answer 9

It must be shown to play a critical role in the disease process.

Question 10

What are 3 strategies for target validation?

Answer 10

Gene Knockout
RNA interference
Small molecules

Question 11

In order to make a new drug for a disease target what must you prove compared to the existing therapy?

Answer 11

You must prove the new agent has a statistically proven clear advantage, not just clinically effective.

A new dosage form, less frequent dosing, new target, increased selectivity, etc…

Question 12

What is a lead compound?

Answer 12

A compound with desired biological activity. This can be characterized and modified to produce another molecule with a better profile of wanted properties and less unwanted side effects.

Question 13

What does the start of a drug discovery project rely on?

Answer 13

The “make and test” cycle.

Question 14

How does Ibrance and Letrozole work to help in breast cancer?

Answer 14

Ibrance inhibits CDK 4 and CDK6 from telling the cell to proliferate

Letrozole decreases the production of estrogen, which prevents it from activating CDK 4 and 6.

Question 15

What are some sources of lead compounds?

Answer 15

Chance Observations
Natural products from folk remedies
Random screening
Substrate Analogues
Structure-based design

Question 16

What is the largest group of recreationally used drugs in the world?

Answer 16

Flunitrazepam

Question 17

In 2008, the FDA approved Thalidomide for the treatment of what in combination with dexamethasone?

Answer 17

Multiple myeloma.

Question 18

What is the primary target of thalidomide?

Answer 18

CRBN (Cereblon)

Question 19

The optimization of what lead to the development of diuretics, such as chlorothiazide?

Answer 19

Sulphanilamide

Question 20

General natural product screening is widely used as a method of finding what?

Answer 20

Lead compounds

Question 21

About __% of drugs in clinical use originate from natural products or their derivaties.

Answer 21

45%

Question 22

What is used to treat River Blindness and Lymphatic Filariasis?

Answer 22

Ivermectin (anti-parasite), which originated from Avermectin.

Question 23

What is the agent that Tu developed into an anti-malarial drug?

Answer 23

Artemisinin

Question 24

What are 3 advantages of natural product screening?

Answer 24

Molecules are structurally diverse

Much precedence as a source of lead compounds: Pharmacologically pre-validated.

Question 25

What are 3 problems with natural product screening?

Answer 25

The mixture of products can hide biological activity.
Isolation of an active component can be hard to do
Structures are complex and difficult to synthesize and identify pharmacophore

Question 26

Are Lovastatin, Pravastatin, and Simvastatin from natural products or synthetic?

Answer 26

Natural products from bacteria and fungus.

Question 27

What does FK506 target?

Answer 27

FKBP and Calcinurin
FDA approved for organ transplant.
Discovered using a systemiatic screening for immunosuppressive activity

Question 28

This drug blocks a protein called FXR receptor that plays a role in cholesterol metabolism.

Answer 28

Guggulsterone

Question 29

How does Psoralen work and what is it used for?

Answer 29

Psoralen is activated by UV light once ingested. This attaches to dividing cancer cells and kills them.

It is used in photodynamic therapy.

Question 30

Can natural substrates or transition-state analogues serve as a lead?

Answer 30

Yes.

Question 31

How does structure-based drug design work?

Answer 31

It uses 3-D X-ray crystallography.

Question 32

What is Veltassa?

Answer 32

It is a potassium binder that is used to treat hyperkalemia.

Question 33

How does Veltassa work?

Answer 33

It increases K+ excretion through binding of K+ int he GI tract.

Question 34

What are 4 ways to optimize lead compounds?

Answer 34

Development of homologous series
Isoteric replacement
Lipinski’s Rule of Five
Chemical modification using data from drug metabolism

Question 35

What is a homologous series?

Answer 35

Changing the size of an alkyl group or of a polymethylene chain.

Question 36

What are Isoteres?

Answer 36

Molecules or ions of similar size containing the same number of atoms or valence electrons.

Group of atoms showing similar physical or chemical properties to a molecule, due to similarities in their size, electronegativity, or stereochemistry.

Question 37

[True/False] Based on the homologous series theory, the duration of local anesthetic activity is decreased as R is changed from a methyl to a butyl group.

Answer 37

False. As you change from a methyl to butyl group you increase the local anesthetic activity.

Question 38

What are Lipinski’s Rule of Five?

Answer 38

There are more than 5 H-bond donors
The MW is over 500
The logP > 5.
There are more than 10 H-bond acceptors.

Question 39

What does Tamoxifen and 4-hydroxytamoxifen do?

Answer 39

They are selective estrogen receptor modulators (SERMs)

Question 40

Where does Valium come from?

Answer 40

It comes from chlordiazepoxide, which was found to be hypnotica and an anticonvulsant.