Enzymology in drug discovery 2

Published on September 23, 2013   66 min

A selection of talks on Pharmaceutical Sciences

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Reversible modes of enzyme inhibition. In this lecture, we will explore how different types of reversible inhibitors can interact with enzymes to form the basis of pharmacological intervention.
This slide summarizes, as a thermodynamic cycle, the different ways that a modulatory compound can interact with an enzyme. If a compound binds to the free enzyme in a way that competes with the substrate, that compound is referred to as a competitive inhibitor. The Kd for that compound is given the special symbol Ki. On the other hand, if the compound binds exclusively to the ES binary complex, that is referred to as an uncompetitive inhibitor. The Kd for that type of inhibitor is given the special symbol αKI. It's also possible for a compound to bind to both the free enzyme and to the ES binary complex. Such a compound is referred to as non competitive. To the describe the affinity of that compound, we have to describe two Kd values. Ki for the affinity of the EI binary complex, and αKi for the ternary ESI complex. Some researchers use the term non-competitive exclusively for situations where the affinity of the inhibitor for the free enzyme and for the ES complex is identical. In other words, an α value of one. They instead use the term mixed inhibition for situations where α is other than one. For convenience, we will use the term non-competitive inhibitor to refer to all situations where the compound has affinity for both the free enzyme and the ES complex, regardless of what the value of α is. You can also see on this slide, that when the ESI ternary complex is formed, it is possible that the reaction will go on to form product with a K_cat value different from that in the absence of inhibitor. The K_cat is modulated in this situation by the constant β. Now in most situations of inhibition, β is equal to zero. That type of inhibition is referred to as dead end inhibition. That is the most useful type of inhibition to go on to pharmacological intervention to form the basis of a drug molecule. If β is less than one but not zero, that situation is referred to as partial inhibition. There are examples of partial inhibitors that are used as drugs, but it's a rare situation. The other possibility is if β is greater than one, in fact, the binding of the compound enhances the catalytic activity of the enzyme. In that case, the molecule would be referred to as an activator rather than an inhibitor. There are examples of metabolites in biology that act as enzymes activators. But we will not speak about those further in these lectures because very rarely is an activator of an enzyme used as a drug molecule.