Knowing Inhibition Modality Is Important for Structure-Based Lead Optimization

5 Knowing Inhibition Modality Is Important for Structure-Based Lead Optimization 

In this chapter we described the thermodynamics of enzyme-inhibitor interactions and defined three potential modes of reversible binding of inhibitors to enzyme molecules. Competitive inhibitors bind to the free enzyme form in direct competition with substrate molecules. Noncompetitive inhibitors bind to both the free enzyme and to the ES complex or subsequent enzyme forms that are populated during catalysis. Uncompetitive inhibitors bind exclusively to the ES complex or to subsequent enzyme forms. We saw that one can distinguish among these inhibition modes by their effects on the apparent values of the steady state kinetic parameters Umax, Km, and VmdX/KM. We further saw that for bisubstrate reactions, the inhibition modality depends on the reaction mechanism used by the enzyme. Finally, we described how one may use the dissociation constant for inhibition (Kh o.K or both) to best evaluate the relative affinity of different inhibitors for ones target enzyme, and thus drive compound optimization through medicinal chemistry efforts. 

Copeland, R. A. (2000), Enzymes A Practical Introduction to Structure, Mechanism and Data Analysis, 2nd ed., Wiley, New York. 

Copeland, R. A., and Anderson, P. S. (2001), Enzymes and Enzyme Inhibitors in Textbook of Drug Design and Discovery, 3rd ed., P. Krogsgaard-Larsen, T. Liljefors, and U. Madsen, eds., Taylor and Francis, New York, pp. 328—363. 

Kenakin, T. (1997), Pharmacologic Analysis of Drug-Receptor Interactions, 3rd ed., Lippincott-Raven, Philadelphia. 

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