High throughput screening methods
Screening large compound libraries from Adrich
•96,384,1536 well micro plates
•Robots for liquid handling
•Automated data capture and an
•Virtual high throughput screening methods
• screening virtual compound libraries (data files-structural information of compounds and target)
• molecule docking
•Automated data analysis tools
•Smaller group is selected for lab investigation
•Cycle begins with identification of structure (“hit”)
In a relevant biological assay
• new analogues with structural modifications are prepared and screened in the biogical assay
• assay results improve ,changes kept, cycle repeated
• changes are detrimental ,changes are discarded, cycle repeated
•Process continues until candidate compound with the desired properties is identified
… to target selection
• financial profit to corporates (pharmaceutical companies)
• target selection set the stage for all future programs
• focus on rare diseases
Identification of technical candidate requires consideration of a variety of properties beyond activity at the biological target of interest
Drug discovery optimises compound so that it has many of the following properties as possible:
•Stable
•Safe
•Selective
•Soluble
•Pharmacokinetics
•Novel
•Active
• Most common form of dementia
• Described in 1906
• >110 years gone, still no treatment
• Potential targets are:
• Beta-secretase (BACE)
• Gamma-secretase
• Glycogen synthase kinase 3beta
(GSK3beta)
• Cyclin-dependent kinase-5 (CDK5)
Priorities disease
CETP cholestryl ester transfer protein target was linked theoretically to lipoprotein metabolism
• Torcetrapib
• Dalcetrapib
• Ancetrapib
Out of the three drugs none was approved:
• CETP was discovered to not be a viable drug target
•Compounds have off target effects
•Pharmokinetic issues
•Torcetrapib- increase in BP and mortality therefore terminated in 2006
•Target biology needs to be thoroughly understood
• Hypertension (the silent killer):
• Diuretics (Midamor (Amiloride)
• Beta-blockers (Tenoretic (Atenolol))
• Angiotensin-converting enzyme (ACE) inhibitors (Capoten
(Captopril)
Other class:
HMG-CoA reductase inhibitors
STATINS by blocking cholesterol production
Lipitor (Atorvastatin)
Zocor (Simvastatin)
Lipinski’s…
• Lipitor
• Lescol
• Crestor both have
• para-flourbenzene ring
and 1,3-diol-carboxylic acid side
chains- otherwise compounds are
quite different to each other
•All above are HMG-CoA reductase
inhibitors
Molecular weight < 500 AMU
log P < five
< five hydrogen bond donors
< five hydrogen bond acceptors
<10 rotatable bonds
Down
Human pharmacology
Healthy volunteers
20–50 subject
Safety margins for further progression
Maximum tolerated dose MTD
•methicillin-resistant Staphlococcus aureus in 1980s
and 1990s.
• Methicillin (Staphcillin) introduced in 1959- to treat penicillin-
resistant bacteria
• 2 years later- resistant strains in European hospitals.
• By 1980, it spread across the globe and costs of bacterial infection
treatment in US alone were- $3-$4 billion annually.
Therapeutic confirmation
Large scale multicentre
<a href="tel:250–1000">250–1000</a>
Efficacy in standard of care
New drug may be approved by the FDA
•Decreases the number of compounds at each level (filtering process)
• A series of qualification that a compound must surpass in order to advance through the process
•Compound that modifies selected target
• exceptionally complex and multifaceted process
• CAS(chemical abstract service database) this database can be used to select compound that is going to be used into drug discovery and development
• use guidance for useful drug-like biological molecules(Lipinski rule)
To examine if hit compounds need follow-up effort or not
• screening decreases number of compounds to few compounds with different structural classes
• structure activity relationship studied
•Synthesise analogues
•Biological testing
… Drugs
Natural products and their derivative:
Taxol
Velban
Adriamycin
• Virus identified- 1983
• 1987- AZT (Retrovir, azidothymidine) approved
• Mechanism- first reverse transcriptase inhibitor
• Over 3 decades- other drugs developed-
• Viread (Tenofovir), Viracept (Nelfinavir), Crixivan (Indinavir) (HIV Protease inhibitor)
• Improved treatment with HAART (highly active antiretroviral therapy)- cocktail treatment
• All-in-one Complera and Stribild
Modern drug discovery changed the course of AIDS epidemic in <30 years
Phase 1
Phase 2
Phase 3
Phase 4
Phase 0
•Drug…
•Some parts of pre-clinical overlap into the stage
Proof of concept
Full development
Registration/launch
Drug…
•Target discovery(target selection)
•Lead discovery
•Lead optimisation (clinical candidate selection)
Throughout drug discovery there is target progression and validation
Identification of a single compound happens
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