7: Tight Binding Inhibition
approaches the total concentration of enzyme ([E]T) in the assay system. This situation is referred to as tight binding inhibition, and it presents some unique challenges for quantitative assessment of…
6: Slow Binding Inhibitors
6.1 Determining kobs: The Rate Constant for Onset of Inhibition The hallmark of slow binding inhibition is that the degree of inhibition at a fixed concentration of compound will vary…
10: Quantitative Biochemistry in the Pharmacological Evaluation of Drugs
To quantify the changes in drug concentration that mark the different phases of the PK profile of a drug, scientists commonly calculate a parameter referred to as the half-life or…
2: Enzyme Reaction Mechanisms
The binary complex ES is commonly referred to as the ES complex, the initial encounter complex, or the Michaelis complex. As described above, formation of the ES complex represents a…
3: Reversible Modes of Inhibitor Interactions with Enzymes
3.1 Enzyme–Inhibitor Binding Equilibria As we have seen before, the enzymatic reaction begins with the reversible binding of substrate (S) to the free enzyme (E) to form the ES complex,…
5: Lead Optimization and Structure–Activity Relationships for Reversible Inhibitors
5.1 Concentration–Response Plots and IC50 Determination In Chapter 4 we briefly introduced the term IC50. Here we will describe its determination and meaning in greater detail. For any enzyme inhibitor…
8: Drug–Target Residence Time
The second type of system is termed an open system. This case is more reflective of how drugs and targets encounter one another in vivo. Here one of the components…
9: Irreversible Enzyme Inactivators
Figure 9.1 Typical enzyme reaction progress curve in the presence of an irreversible enzyme inactivator, highlighting the initial velocity region (vi) and the fact that the terminal velocity (vs) is…
4: Assay Considerations for Compound Library Screening
4.1.2 Total, Background, and Specific Signal In the preceding section we defined the total signal and background signal as they relate to construction of a calibration or standard curve for…
1: Why Enzymes as Drug Targets?
Dehydrogenase Lovastatin and other statins HMG-CoA reductase Cholesterol lowering Methotrexate Dihydrofolate reductase Cancer, immunosuppression Nitecapone Catechol-O-methyltransferase Parkinson’s disease Norfloxacin DNA gyrase Urinary tract infections Omeprazole H+, K+ ATPase Peptic ulcers…
