Fragment based drug discovery

What is a diagram showing the process of drug discovery?

Each cog represents where a decision must be made

What is a diagram showing the advances in technology?

Blue = cannot speed up those processes, try to speed up red

What processes are included in target identification?

Genomics, proteomics, metabolomics, NMR, X-ray to validate if the compounds would bind

What is high-throughput screening?

Screening of 1000s of compounds quickly with an automated process to try and optimise target and finds activity against an assay

How is synthesis of potential leads done?

1000s of analogues made in a short period and figure out what structures have the best/worst hits

What information does high throughput screening give/not give?

Gives info on biological activity but not how it fits into a receptor

What is a diagram representing the high throughput screening process?

What does high throughput screening require?

Large libraries of compounds

What is a diagram showing the fragment based drug discovery?

What does fragment based drug discovery use for screening?

Screening that isn’t cell based and not large molecules

What are the fragments in fragment based drug discovery?

Smaller parts that fit into the receptor/target and see how the small fragments bind

What is a comparison of HTS and fragment based approaches?

• HTS uses the hypothetical fragments and reacts all of those together to make 10^8 potential compounds, unknown what is binding in the target, 100000000 molecules made, 100 hits made

• Fragment looks at the fragments and screens individual ligands to see what binds for precise info before reacting together, only makes 10,100 compounds with 100 hits

Why is a fragment based approach better?

Much better return on efforts, screens less compounds, easier to get more effective compounds and a better lead

What is a low quality hit from HTS?

High molecular weight compounds that occupy a large volume within the target

What are the drawbacks of low quality hits from HTS?

has a high potential for low quality hits and false positives or negatives

What is the association to the target driven by with low quality hits in HTS?

Thermodynamics and not the number of interactions with the target site - does it bind and how strongly it binds

What is a table showing the differences between fragment based and HTS screening?

What is fragment evolution/growing?

An initial fragment is optimised to bind to adjacent regions of the desired target site

What is fragment linking?

2 or more fragments bind to proximal parts of the target site and are joined together to give a larger molecule with higher affinity for the target

What is fragment self-assembly?

Fragments with complementary functional groups are allowed to react together in the presence of the protein target and the most potent larger molecule is chosen

What is fragment optimisation?

Rational approaches which are used to optimise drug-like properties of a lead, other than just the receptor binding affinity

What are growth vectors in fragment evolution/growing?

Points on the fragment where additional atoms, functional groups, linkers or other fragments can be attached are identified

What is a diagram showing potential growth vectors?

What are growth vectors guided by?

target site and fragment hit structure

What is a diagram representing fragment linking?

Joined with a larger molecule

What happens in fragment self assembly?

2 fragments have complimentary functional groups that react together in the target site

What happens in fragment optimisation?

Lead compound is re-engineered to optimise a specific property

What is a diagram showing fragment merging?

Parts of both original molecules are found in the new lead

What does a more powerful magnet give in NMR for drug discovery?

Better structural information

Why is NMR used in drug discovery?

Helps to determine distances between atoms, 3D structures of proteins

How can NMR be adapted to look at how a drug would bind in the body?

Can be done in aqueous solution to represent body conditions

What is a diagram showing ligand binding in a receptor for NMR?

When bound - ligand will no longer be free in solution and will take on characteristics of protein R.

What phenomena allow accurate measurement of distances in NMR?

Change in chemical shift and polarisation transfer

What is the vemurafenib example for fragment based drug discovery?

Kinase inhibitor

What is the venetoclax example?