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Printable Handouts
Navigable Slide Index
- Introduction
- Goals
- Key references and disclaimer
- Reversible modes of enzyme inhibition
- Enzyme-inhibitor binding equilibria
- Effects of inhibitors on catalysis steps
- Inhibition modalities
- Competitive enzyme inhibitors in clinical use
- Lovastatin inhibition of HMG-CoA reductase
- Captopril and enalaprilate inhibition of ACE
- Competitive inhibitors of HIV protease
- Noncompetitive enzyme inhibitors in clinical use
- NNRTI inhibition of HIV reverse transcriptase
- Uncompetitive enzyme inhibitors in clinical use
- Methotrexate inhibition of DHFR
- Dissociation constants: DHFR-ligand complexes
- DHFR interactions with methotrexate and DHF
- Inhibition of 5-alpha reductase (1)
- Inhibition of 5-alpha reductase (2)
- Dead end inhibitor modality
- Advantages of reversible inhibition modalities
- Common non-classical modes of inhibition
- Enzyme assays for inhibitor discovery
- Assay criteria for screening
- Factors that can affect enzyme assays
- Laboratory measures of enzyme reactions
- Balanced assay conditions
- Balanced conditions and physiological context
- Screening for inhibitors of DHFR (1)
- Screening for inhibitors of DHFR (2)
- Measure of signal robustness
- Hit declaration criteria
- False positives
- Promiscuous inhibitors
- HTS compound follow-up
- Enzyme inhibitors during lead optimization
- Compound evaluation flowchart
- Concentration-response plots
- Compound IC50 values
- Effect of substrate on IC50
- Cheng-Prusoff relationships
- Hill coefficient
- Why report Hill coefficients?
- Biphasic binding
- Non-ideal 4-parameter fits
- Non-ideal 2-parameter fits
- Testing for inhibitor reversibility
- Defining inhibitor modality and Ki
- Selectivity in terms of relative Ki values
- The value of knowing inhibitor modality
- Suggestions for data reporting
- Cellular effects and target enzyme inhibition
- Cellular effects and target engagement
- Enzyme-cellular correlation plot
- Summary
Topics Covered
- Enzymes as targets for drug discovery
- Protein-ligand binding equilibria
- Enzyme reaction mechanisms
- Structure and function of enzyme active sites
- Measuring enzyme velocity in the laboratory
- Reversible modes of enzyme inhibition
- Enzyme inhibition as a mechanism of pharmacological intervention in disease
- Clinical value of different inhibition modalities
- Non-classical inhibition
- Enzyme assays and screening criteria
- Lead optimization
- Summary: basic information to look for
Links
Series:
Categories:
Talk Citation
Copeland, R. (2013, September 23). Enzymology in drug discovery 2 [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved January 19, 2021, from https://hstalks.com/bs/2638/.Publication History
Financial Disclosures
- Prof. Robert Copeland has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Enzymology in drug discovery 2
Published on September 23, 2013
66 min