Fragment-Based Drug discovery

what is rational drug design

the aim is to increase selectivity of the drug for the target site and increase the activity of the drug

consequently this should lead to a lower dosage required and fewer side effects

strategies for rational drug design

• vary alkyl, aryl and other substituents

• chain extension and contraction

• ring expansion, contraction and variation

• bio - isosteric replacement

• simplification

• rigidification

advances in technoolgy

target identification

• genomics, proteomics, metabolomics, NMR, Xray

Synthesis of potential leads

• combinational chemistry

High - throughput screening

• mol bol, microbiology

Active compounds

Candidate optimisation

Clinical candidate

clinical trials - informatics

market drug

what is high-throughput screening HTS

• hit generation

• lead generation and optimization

• candidate

• tells you whether a molecule has biological activity via different screens

• need a lot of compounds

• automated

fragment- based drug discovery

small fragments that may fit into our receptors

• screening

• confirmation methods - seeing key interactions before going on to develop the finished drug molecule

HTS vs Fragment based approach

traditional method

• 10000 compounds

• react together to create more compounds

• then screen

• find some compounds that have activity

• 100,000,000 finish so not very useful

newer method

• synthesise 1000 frgaments

• screen individually against the receptor we want

• then link or combine successful ones

• then your left with 10100 molecules so much more narrowed down

low quality hit from HTS

• high molecular weight compounds that occupy a large volume in the target

• high potential for low quality hits and false +ve and -ve responses

what is fragment evolution/ growing

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

what is fragment linking

Two (or more) fragments, which bind to
proximal parts of the target site, 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 receptor
binding affinity

NMR techniques in drug discovery

• when bound the ligand L will no longer be free in solution and will take on the characteristics of the target protein R

• Various phenomena such as change in chemical shift and polarisation transfer, enable the accurate measurements of distances and the 3-d shape of the ligand-protein complex, complementary to x rays