Drug discovery

Question 1

What’s a lead compound?

Answer 1

A compound that affects the drug target in a promising way and may be developed into a drug candidate.

Question 2

What’s Km?

Answer 2

The [Substrate] at which the reaction speed is at 50%. This also means the [Substrate] at which 50% of the enzymes are active.

Question 3

What’s IC50?

Answer 3

The inhibitor concentration required to achieve 50% decrease of reaction speed.

Question 4

What’s target validation?

Answer 4

It’s validation of drug targets to nersure that it’s important in the disease that you aim to treat.

Question 5

In short, how does the screening cascade look like?

Answer 5

Primary assay
Artefact assay
Primary assay
Secondary assay

Question 6

What’s a primary assay?

Answer 6

HTS used to identify potential drug candidates.

Question 7

What’s an artifact assay?

Answer 7

An assay that confirms the activity from the primary assay is due to on-target effects and not from elsewhere.

Question 8

What’s a secondary assay?

Answer 8

A more specific assay than the primary assays, used to find mechanisms of actions and the like.

Question 9

Describe HTS

Answer 9

Screening thousands - millions of compounds in short time. Will produce a large number of false positives. Expensive.

Question 10

Describe fragment-based lead generation

Answer 10

It’s HTS with small fragments instead of larger molecules. The reasoning behind FBL is that the small fragments won’t be sterically hindered by molecular structures. You can get an understanding of the chemical attributes required in the interaction between receptor and compound.

Question 11

Describe fast-follower

Answer 11

Develop a drug that is similar to one that a competitor has dewveloped. This is a fast way to develop drugs, you skip all the hurdles.

Question 12

Describe GPCR drug targets, give examples of assays

Answer 12

GPCRs are 7 transmembranal alpha helices. They signal via 3 G-proteins.

Assays
- Filtration assays
- Calcium immobilization assays

Question 13

Describe ion channel drug targets and what assays you can run on them

Answer 13

IOn channels are often voltage-gated. Otherwise they are ligand-stimulated.

Assays
- Manual patch clamp (golden standard)
- Ion flux assay (saturate cell w/ ion-sensitive dye, see it react). Can be problematic as dye may react w/ the drug.

Question 14

Describe enzyme drug targets and the assays used on them

Answer 14

Assays
- Clot lysis assays
- Colorimetric assays
- Kinase assays

Question 15

What’s the DMTA cycle?

Answer 15

Design: Design new compounds
Make: Organically synthesise the compounds
Test: yes
Analyze: Find ways to optimize.