Finding Drugs

Question 1

In what ways can drugs be discovered?

Answer 1

• From natural products (see above).
• Testing of accumulated compounds from other compounds (w/ associated compounds).
• Combinatorial chemistry (large groups of compounds).
• Computational chemistry/in silico (virtual screening).

Question 2

Discovery of drugs from natural products is described as ‘low hanging fruit’, what does this mean?

Answer 2

Drugs discovered from natural products were the easiest to find and isolate into medicinal products. As these are discovered, new discoveries become harder and harder.

Question 3

Describe the characteristics of modern pharmaceutical R&D.

Answer 3

Modern pharmaceutical R&D is about efficiency and removing reliance on cleverness and luck.

Question 4

Taxol (paclitaxel) is a drug developed by Bristol-Myers Squibb; what is it used for and from what source was it discovered?

Answer 4

It is an anti-cancer drug isolated from the Pacific Yew tree by the US National Cancer Institute in 1967.

Question 5

Which cancers can Taxol (paclitaxel) be used to treat?

Answer 5

Taxol is used to treat patients with lung, ovarian, breast, head, and neck cancers as well as advanced Kaposi’s sarcoma. It is relatively selective for rapidly dividing cancer cells.

Question 6

How does Taxol (paclitaxel) work?

Answer 6

It works by stabilising microtubules and inhibiting cell division.

Question 7

What proportion of small molecule drugs comes from natural products or are synthetically derived from natural products?

Answer 7

One quarter.

Question 8

What is a ‘me-too’ drug?

Answer 8

A ‘me-too’ drug is one which is similar to a patented drug in the effects it has, however, is different enough that it falls outside of the patent.

Question 9

Describe high throughput screening.

Answer 9

This process features machines screening 1000s of compounds quickly. However, this process has a poor chance of generating actual ‘hits’; leading to a chance of random errors. HTS is done initially and then HCS is carried out.

Question 10

Describe high content screening.

Answer 10

This is a more traditional and labour-intensive process of complex manual assays. This process may be slow but is more reliable, showing the real ‘hits’ from the ones generated in HTS.

Question 11

Describe computer-aided compound screening.

Answer 11

CACS can be used to reduce the search space, yet not miss anything, whilst making the process more efficient and reliable. CACS impacts compound selected from internal and external compound collections, selection of fragments for fragment-based design, and the design of libraries.

Question 12

Describe virtual screening.

Answer 12

Replaces expensive and time-consuming blind searches with computer-guided alternatives.

Question 13

Give some examples of virtual screening techniques.

Answer 13

• 2D virtual screening.
• Pharmacophore screening.
• Structure-based automated protein docking (SB-APD).

Question 14

Give three different compound selection techniques.

Answer 14

Drug-like, lead-like, ligand-like.

Question 15

Describe drug-like compound selection.

Answer 15

Remove reactive molecules, filter on properties (Lipinski’s rule of 5, ASA, Predicted properties), predict ‘drug-ness’.

Question 16

Describe lead-like compound selection.

Answer 16

More restrictive filtering.

Question 17

Describe ligand-like compound selection.

Answer 17

The similarity to known ligands, ligands of related receptors, privileged fragments.

Question 18

Put drug-like, lead-like, and ligand-like compound selection into the order of greatest hits to fewest hits.

Answer 18

Drug-like, lead-like, ligand-like.

Question 19

Give some characteristics of good drug candidates.

Answer 19

Features common to known drugs (few drugs are acyclic), Selected compounds should have features common to those drugs which bind a particular receptor class.

Question 20

Give some characteristics of drug candidates which are bad but still possibly useful in the right circumstances.

Answer 20

• Heavy metal ions (E.g. Hg or U).
• Inorganic structures.
• Organometallics.
• Reactive groups (E.g. Michael acceptors (May be used if they are unreactive until they bind)).
• Groups not consistent with the properties of good drugs (E.g. Long alkyl chains).
• Promiscuous inhibitors (Molecules that regularly come up as hits).

Question 21

Give some characteristics of poor drug candidates, which may have no use.

Answer 21

• Synthetically intractable molecules.
• Too big.
• Too complex.
• Too many H-bond donors and acceptors.
• Too difficult and time consuming to make.

Question 22

Describe Lipinski’s rule of 5.

Answer 22

1. Maximum of 5 hydrogen bond donors (nitrogen or oxygen with 1+ hydrogen atoms).
2. Maximum of 10 hydrogen bond acceptors (nitrogen or oxygen).
3. Molecular weight <500.
4. Octanol-water partition coefficient (LogP) <5.