Markku D. Hämäläinen
Senior Scientist in Chemometrics, Div. Protein Analysis, R&D GE Healthcare Bio-Sciences AB, Uppsala, Sweden

Abstract:

Binding strength, affinity (KD) can be broken down into kinetic rate constants that reflect drug-target recognition (the association rate constant, kon) and the stability of the resulting complex (dissociation rate constant, koff). The relationship between these properties can be described as KD = koff/ kon. The off-rate has been recognized for some time as a key parameter for understanding pharmacokinetic and dynamic (PKPD) properties of drugs1-2. A slow off-rate can prolong the therapeutic effect both by tight binding and by “hiding” the drug from enzymatic degradation and clearance by keeping it out of the circulation. High off-rate selectivity can also minimize side effects caused by off-target binding. 

The importance of on-rate is less recognized, however, and even (erroneously) thought to be constant (diffusion rate limited) for small molecules. If the on-rate is too low in relation to its bioavailability, the drug will never bind to the target, and affinity/dissociation rate is then a false indication of the potency of the drug.

 In this lecture, I will discuss the effects of different on/off-rate combinations in relation to the bioavailable concentration of leads and how this influences binding to the target protein and the residence time of the drug in the binding site. Examples will be given to highlight the importance of on-rate – Without “on” there is no “off”!