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MPharm 2 - PH2114 > Drug Discovery 1 > Flashcards

Drug Discovery 1 Flashcards

1
Q

What is a lead compound?

A

The improved molecule via physicochemical, pharmacologic, toxicologic, and pharmacokinetic modifications of a “hit”

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2
Q

What might biologists discover?

A

A novel biological target

  • an enzyme
  • a receptor
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3
Q

What is a drug?

A

A molecule that can be designed and synthesised

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4
Q

What are the two classes of drugs?

A

Chemical drugs

Biological drugs

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5
Q

Describe chemical drugs.

A

Chemical Drugs
Range from simple inorganic salts to complex organic molecules.
Organic drug molecules often referred to as small molecules these are ‘drug-like’ organic compounds with a molecular weight approximately < 500.
When discovered, referred to as a ‘New Chemical Entity’ (NCE).

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6
Q

Describe biological drugs.

A

Biological Drugs (“Biologics”).
Also known as large molecule drugs. Usually proteins such as peptides or antibodies (but could be a nucleic acid, e.g. gene therapy).
When discovered, referred to as a ‘New Biological Entity’ (NBE).

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7
Q

What is a small organic drug referred to once discovered?

A

A New Chemical Entity (NCE)

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8
Q

What is a large molecule drug referred to once discovered

A

A New Biological Entity (NBE)

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9
Q

What are New Chemical Entities and New Biological Entities known as when considered together ?

A

New Molecular Entities (NMEs)

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10
Q

Where do novel Small Molecules come from?

A 
Natural sources or derived from nature
Derived from endogenous compounds
- biochemical
Synthetic drugs
- derived from screening or rational medicinal chemistry
Serendipity
'Me too'
In silico drug design
- molecular modelling
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11
Q

Why are small lead compounds often not suitable drug molecules?

A

Do not have suitable properties to use clinically
- poor aqueous solubility
- low activity
Usually require optimisation

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12
Q

Historically, what was the only source of medicines?

A

Nature

  • herbal medicine
  • Chinese medicine
  • minerals
  • mercury
  • arsenic
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13
Q

What is a Natural Product?

A

A discrete compound produced by a living organism

- very valuable to medicine

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14
Q

Give examples of medicinal natural products that have been derived from plants

A

Paclitaxel- breast and ovarian cancer.
Isolated from bark of the yew tree.

Quinine- malaria.
Isolated from bark of cinchona tree

Digoxin - Digoxin, heart failure, arrhythmias.
Leaves of the Foxglove.

Morphine- analgesic.
Contained within resin from poppy seeds.

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15
Q

Give an example of a drug that is derived from a natural product

A

Aspirin

- willow bark used from 400BC to relieve fever

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16
Q

How is salicin converted into aspirin?

A

Hydrolysis removes sugar group
Oxidation -> salicylic acid
Acetylation -> aspirin

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17
Q

How is morphine converted to diamorphine?

A

Acetylation

18
Q

Why might biochemicals or natural ligands within the body not make good lead compounds prior to analogue synthesis?

A

Natural ligand may

  • have undesirable duration of action
  • be excreted or metabolised too quickly
  • be chemically unstable
19
Q

Why are small lead compounds often not suitable drug molecules?

A

Do not have suitable properties to use clinically
- poor aqueous solubility
- low activity
Usually require optimisation

20
Q

Why might biochemicals or natural ligands within the body make good lead compounds after analogue synthesis?

A

Natural ligand beforehand may

  • have undesirable duration of action
  • be excreted or metabolised too quickly
  • be chemically unstable
21
Q

What does changing the structure of an endogenous lead compound allow?

A

Determination of structure activity relationships (SAR)

22
Q

Why must analogues of natural ligands retain their core structures?

A

Allow binding to the biological target

23
Q

What is methotrexate?

A

Anti-proliferative drug
- blocks the effect of folic acid
- essential for cell growth
Discovered from a collection of compounds all with structural similarities to folic acid

24
Q

Which synthetic derived drugs were noted for their anti-bacterial properties in the early 1900s?

A

azo dyes

25
Q

What was added to azo dye to increase the binding of the dye to the wool?

A

Sulphonamide group

- SO2NH2

26
Q

What did the sulphonamide azo dye compound decompose into?

A

Sulfanilamide

- an excellent antibiotic

27
Q

Why are sulphonamides now largely discontinued as antibiotics?

A

Resistance
Side effects
More effective agents available

28
Q

What is sulfadiazine still used for?

A

Rheumatic fever
a disease that can affect the heart, joints, brain, and skin. Rheumatic fever can develop if strep throat and scarlet fever infections are not treated properly.

29
Q

What is co-trimoxazole (Sulfamethoxazole and Trimethoprim) currently used for?

A

Pneumonia and Toxoplasmosis

Pneumonia is an infection that inflames the air sacs in one or both lungs

Toxoplasmosis is a common infection that you can catch from the poo of infected cats, or infected meat
flu like symptoms

30
Q

How many molecules were screened whilst trying to find a better inflammatory alternative to aspirin or corticosteroids in the 1950s?

A

Ibuprofen, marketed in 1969 was non-toxic (no liver accumulation) and safe (non-prescription in 1983). Approximately 20 years to develop, from the synthesis and screening of 650 synthetic analogues.

31
Q

Give an example of a drug discovered using computer aided (in silico) drug design

A

Tamiflu

32
Q

What was the lead compound in developing Tamiflu?

A

Sialic acid

  • a computer model showed it interacted with neuraminidase by bonding to three arginine residues via a carboxylic acid group
  • the target viral enzyme
33
Q

What is Tamiflu?

A

An ethyl ester prodrug allowing oral formulation

- ester is cleaved by plasma esterase enzymes to unmask the important carboxylic acid

34
Q

What are the advantages to ‘me too’ drug design?

A

An easy way to design a drug cheaply is to copy another product

35
Q

What is a ‘me too’ drug?

A

One with a similar structure to an existing drug, modified enough to make the compound novel but not so much that the activity is affected

36
Q

what does serendipity mean ?

A

Serendipity “the occurrence and development of events by chance in a happy or beneficial way”

37
Q

Give an example of a Serendipitous drug design?

A

Penicillin

  • 1928 Alexander Fleming goes on holiday
  • spores from Penicillium mould contaminate a culture plate containing Staphylococci bacteria
  • the penicillium mould kills the bacteria on contact
  • a chemical in the mould is killing the bacteria

1939 - active substance finally isolated
1944 - used in the clinic

38
Q

Give an example of a drug discovered by utilising side effects

A

Sulfanilamide caused hypoglycaemia
- low blood sugar
It was also a mild diuretic

Led to development of tolbutamide (diabetes)
and chlorothiazide (diuretic)
39
Q

What is a pharmacophore?

A

Portion of a drug required for activity

If the pharmacophore is altered or absent the molecule will lose the associated properties.

40
Q

How did sildenafil become the drug commonly known as “viagra” through the use of its side effects?

A

Sildenafil was designed as a vasodilator to treat angina and hypertension
1992 - performed very poor in clinical trial to treat coronary heart disease
30 men refused to return unused medicine
- beneficial and unknown side effect
- 1998 - drug launched as a treatment for erectile dysfunction

MPharm 2 - PH2114 (32 decks)

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